Pyrrole compounds

ABSTRACT

The present invention relates to a compound represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein A is pyridyl group having at least one substituent 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are each a hydrogen atom, a halogen atom, a C 1-6  alkyl group optionally substituted by halogen or a C 1-6  alkoxy group optionally substituted by halogen, R 4  and R 6  are each a hydrogen atom, a halogen atom or a C 1-6  alkyl group optionally substituted by halogen, R 5  is a hydrogen atom, a halogen atom, a C 1-6  alkyl group optionally substituted by halogen or a C 1-6  alkoxy group optionally substituted by halogen, and R 7  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by halogen or a salt thereof, or a pharmaceutical composition containing the same.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to pyrrole compounds having an acidsecretion suppressive activity.

BACKGROUND OF THE INVENTION

Proton pump inhibitors represented by omeprazole, which suppress gastricacid secretion for the treatment of peptic ulcer, reflux esophagitis andthe like, have been widely used in clinical situations. However, theexisting proton pump inhibitors are associated with problems in terms ofeffect and side effects. To be specific, since the existing proton pumpinhibitors are unstable under acidic conditions, they are oftenformulated as enteric preparations, in which case several hours arerequired before onset of action, and about 5 days to exhibit maximumefficacy by consecutive administration. In addition, since the existingproton pump inhibitors show variable treatment effects due to metabolicenzyme polymorphism and drug interaction with medicaments such asdiazepam and the like, an improvement has been desired.

As pyrrole compounds having a proton pump inhibitory action, patentreference 1 describes a compound represented by the formula:

wherein X and Y are the same or different and each is a bond or a spacerhaving 1 to 20 atoms in the main chain, r¹ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, r²,r³ and r⁴ are the same or different and each is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedthienyl group, an optionally substituted benzo[b]thienyl group, anoptionally substituted furyl group, an optionally substituted pyridylgroup, an optionally substituted pyrazolyl group, an optionallysubstituted pyrimidinyl group, an acyl group, a halogen atom, a cyanogroup or a nitro group, and r⁵ and r⁶ are the same or different and eachis a hydrogen atom or an optionally substituted hydrocarbon group. Inaddition, as a pyrrole compound having a proton pump inhibitoryactivity, patent document 2 describes a compound represented by theformula

wherein r⁷ is a monocyclic nitrogen-containing heterocyclic groupoptionally fused with a benzene ring or heterocycle, the monocyclicnitrogen-containing heterocyclic group optionally fused with a benzenering or heterocycle optionally has substituent(s), r⁸ is an optionallysubstituted C₆₋₁₄ aryl group, an optionally substituted thienyl group oran optionally substituted pyridyl group, r⁹ and r¹⁰ are the same ordifferent and each is a hydrogen atom or one of r⁹ and r¹⁰ is a hydrogenatom and the other is an optionally substituted lower alkyl group, anacyl group, a halogen atom, a cyano group or a nitro group, and r¹¹ isan alkyl group, and the like.

Furthermore, as a therapeutic drug for neoplastic diseases or autoimmunediseases, patent reference 3 describes a compound represented by theformula:

wherein r⁷ is aryl, aralkyl, heteroaryl or the like, r⁸ is aryl,heteroaryl or the like, and r⁹ is aryl, heteroaryl, optionallysubstituted aminomethyl or the like.Patent reference 1: WO 2006/036024Patent reference 2: WO 2007/026916Patent reference 3: WO 2004/103968

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

A medicament that effectively suppresses gastric acid secretion as knownproton pump inhibitors, which is improved in instability under acidicconditions, dispersion of effects due to metabolic enzyme polymorphismand drug interaction, which are problems of known proton pumpinhibitors, is expected to show more superior treatment effect on pepticulcer, reflux esophagitis and the like. As the situation stands,however, a proton pump inhibitor capable of sufficiently satisfyingthese requirements has not been found. It is therefore an object of thepresent invention to provide a compound having a superior acid secretionsuppressive effect (particularly, proton pump inhibitory effect), whichhas been improved in these problems.

Means of Solving the Problems

The present inventors have conducted various studies and found that acompound represented by the formula (I):

wherein the symbols are to be defined below, or a salt thereof[hereinafter to be sometimes abbreviated as compound (I)] unexpectedlyhas a very strong proton pump inhibitory effect, and is fullysatisfactory as a medicament, which resulted in the completion of thepresent invention.

Accordingly, the present invention relates to the following.

[1] A compound represented by the formula (I)

wherein A is a pyridyl group having at least one substituent:

wherein R¹, R² and R³ are each a hydrogen atom, a halogen atom, a C₁₋₆alkyl group optionally substituted by halogen or a C₁₋₆ alkoxy groupoptionally substituted by halogen, R⁴ and R⁶ are each a hydrogen atom, ahalogen atom or a C₁₋₆ alkyl group optionally substituted by halogen, R⁵is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group optionallysubstituted by halogen or a C₁₋₆ alkoxy group optionally substituted byhalogen, and R⁷ is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by halogen, or a salt thereof,[2] the compound of the above-mentioned [1], wherein A is represented bythe formula (A-1) wherein R¹ and R³ are both hydrogen atoms, and R² is ahalogen atom, a C₁₋₆ alkyl group optionally substituted by halogen or aC₁₋₆ alkoxy group optionally substituted by halogen, or a salt thereof,[3] the compound of the above-mentioned [2], wherein R² is a C₁₋₆ alkylgroup or a C₁₋₆ alkoxy group, or a salt thereof,[4]1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof,[5]1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof,[6]1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof,[7]1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof,[8]1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof,[9] a prodrug of the compound of the above-mentioned [1] or a saltthereof,[10] a pharmaceutical composition comprising the compound of theabove-mentioned [1] or a salt thereof or a prodrug thereof,[11] the pharmaceutical composition of the above-mentioned [10], whichis an acid secretion inhibitor,[12] the pharmaceutical composition of the above-mentioned [10], whichis a potassium-competitive acid blocker,[13] the pharmaceutical composition of the above-mentioned [10], whichis an agent for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis, symptomaticgastroesophageal reflux disease (symptomatic GERD), Barrett's esophagus,functional dyspepsia, gastric cancer, stomach MALT lymphoma, or ulcercaused by non-steroidal anti-inflammatory drug, gastric hyperacidity orulcer due to postoperative stress; or an inhibitor of uppergastrointestinal bleeding due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress,[14] a method for treating or preventing peptic ulcer, Zollinger-Ellisonsyndrome, gastritis, reflux esophagitis, symptomatic gastroesophagealreflux disease (symptomatic GERD), Barrett's esophagus, functionaldyspepsia, gastric cancer, stomach MALT lymphoma, or ulcer caused bynon-steroidal anti-inflammatory drug, gastric hyperacidity or ulcer dueto postoperative stress; or a method of inhibiting uppergastrointestinal bleeding due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress, which comprises administeringan effective amount of the compound of the above-mentioned [1] or a saltthereof or a prodrug thereof to a mammal,[15] use of the compound of the above-mentioned [1] or a salt thereof ora prodrug thereof for the production of an agent for the prophylaxis ortreatment of peptic ulcer, Zollinger-Ellison syndrome, gastritis, refluxesophagitis, symptomatic gastroesophageal reflux disease (symptomaticGERD), Barrett's esophagus, functional dyspepsia, gastric cancer,stomach MALT lymphoma, or ulcer caused by non-steroidalanti-inflammatory drug, gastric hyperacidity or ulcer due topostoperative stress; or an inhibitor of upper gastrointestinal bleedingdue to peptic ulcer, acute stress ulcer, hemorrhagic gastritis orinvasive stress, and[16] the compound of the above-mentioned [1], wherein A is a pyridylgroup having at least one substituent, the formula (A-1) or the formula(A-2) wherein one of R¹ and R³ is a halogen atom, a C₁₋₆ alkyl groupoptionally substituted by halogen or a C₁₋₆ alkoxy group optionallysubstituted by halogen, and the other is a hydrogen atom, a halogenatom, a C₁₋₆ alkyl group optionally substituted by halogen or a C₁₋₆alkoxy group optionally substituted by halogen, R² is a hydrogen atom, ahalogen atom, a C₁₋₆ alkyl group optionally substituted by halogen or aC₁₋₆ alkoxy group optionally substituted by halogen, R⁴ and R⁶ are eacha hydrogen atom, a halogen atom or a C₁₋₆ alkyl group optionallysubstituted by halogen, R⁵ is a hydrogen atom, a halogen atom, a C₁₋₆alkyl group optionally substituted by halogen or a C₁₋₆ alkoxy groupoptionally substituted by halogen, and R⁷ is a hydrogen atom or a C₁₋₆alkyl group optionally substituted by halogen, or a salt thereof.

EFFECT OF THE INVENTION

Compound (I) of the present invention shows a superior proton pumpinhibitory effect. Conventional proton pump inhibitors such asomeprazole, lansoprazole and the like are converted to active forms inan acidic environment of gastric parietal cells and form a covalent bondwith a cysteine residue of H⁺/K⁺-ATPase, and irreversibly inhibit theenzyme activity. In contrast, compound (I) inhibits proton pump(H⁺/K⁺-ATPase) activity in a reversible and K⁺ competitive manner, andconsequently suppresses acid secretion. Therefore, it is sometimescalled a potassium-competitive acid blocker (P-CAB), or an acid pumpantagonist (APA). Compound (I) rapidly exhibits the action and shows themaximum efficacy from the initial administration. Furthermore, itsmetabolism is less influenced by metabolic polymorphism and variation ofefficacy among patients is small. In addition, it has been found thatcompound (I) is designed to have a characteristic chemical structurewherein (i) the substituent at the 5-position of pyrrole ring is a2-F-3-pyridyl group, (ii) the substituent at the 4-position of pyrrolering is a fluorine atom, and (iii) the 1-position of pyrrole ring is a2-pyridylsulfonyl group or 3-pyridylsulfonyl group having at least onesubstituent, and such chemical structure is conducive to a strong protonpump inhibitory activity, and significantly decreases cytotoxicity.Furthermore, it is characterized in that substitution of the 4-positionof pyrrole ring by a fluorine atom in compound (I) lowers basicity (pKavalue) of methylaminomethyl moiety due to an electron withdrawing effectof the fluorine atom, and decreases the risk of toxicity expressionderived from strong basicity, and that introduction of at least onesubstituent into 2-pyridyl group or 3-pyridyl group in A of compound (I)controls the duration of action optimally. Hence, the present inventioncan provide a clinically useful agent for the prophylaxis or treatmentof peptic ulcer (e.g., gastric ulcer, duodenal ulcer, anastomotic ulcer,ulcer caused by non-steroidal anti-inflammatory drug, ulcer due topostoperative stress etc.), Zollinger-Ellison syndrome, gastritis,erosive esophagitis, reflux esophagitis, symptomatic gastroesophagealreflux disease (Symptomatic GERD), Barrett's esophagus, functionaldyspepsia, gastric cancer, stomach MALT lymphoma or hyperacidity; or asuppressant of upper gastrointestinal bleeding due to peptic ulcer,acute stress ulcer, hemorrhagic gastritis or invasive stress; and thelike. Since compound (I) shows low toxicity and is superior inwater-solubility, in vivo kinetics and efficacy exhibition, it is usefulas a pharmaceutical composition. Since compound (I) is stable even underacidic conditions, it can be administered orally as a conventionaltablet and the like without formulating into an enteric-coatedpreparation. This has an advantageous consequence that the preparation(tablet and the like) can be made smaller, and can be easily swallowedby patients having difficulty in swallowing, particularly the elderlyand children. In addition, since it is free of a sustained releaseeffect afforded by enteric-coated preparations, onset of suppression ofgastric acid secretion is rapid, and symptoms such as pain and the likecan be alleviated rapidly.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows results of perfusate pH measurement test in anesthetizedrat stomach perfusion model in Example 2.

FIG. 2 shows results of perfusate pH measurement test in anesthetizedrat stomach perfusion model in Example 5.

FIG. 3 shows results of perfusate pH measurement test in anesthetizedrat stomach perfusion model in Example 24.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, examples of the “halogen atom” and“halogen” include a fluorine atom, a chlorine atom, a bromine atom andan iodine atom. In the formula (I), A is a pyridyl group having at leastone substituent. Examples of the “pyridyl group having at least onesubstituent” for A include a group represented by the formula

wherein R¹, R² and R³ are each a hydrogen atom, a halogen atom, a C₁₋₆alkyl group optionally substituted by halogen or a C₁₋₆ alkoxy groupoptionally substituted by halogen, R⁴ and R⁶ are each a hydrogen atom, ahalogen atom or a C₁₋₆ alkyl group optionally substituted by halogen, R⁵is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group optionallysubstituted by halogen or a C₁₋₆ alkoxy group optionally substituted byhalogen, and R⁷ is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by halogen. By “having at least one substituent” is meantthat at least one of R¹, R² and R³ in the partial structure (A-1) is nota hydrogen atom, and at least one of R⁴, R⁵, R⁶ and R⁷ in the partialstructure (A-2) is not a hydrogen atom.

The “C₁₋₆ alkyl group optionally substituted by halogen” for R¹, R², R³,R⁴, R⁵, R⁶ or R⁷ is a C₁₋₆ alkyl group optionally having 1 to 5(preferably 1 to 3) halogen atoms (e.g., fluorine atom, chlorine atom,bromine atom, iodine atom), and examples thereof include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, trifluoromethyl andthe like.

The “C₁₋₆ alkoxy group optionally substituted by halogen” for R¹, R², R³or R⁵ is a C₁₋₆ alkoxy group optionally having 1 to 5 (preferably 1 to3) halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom,iodine atom), and examples thereof include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy,fluoromethoxy, trifluoromethoxy and the like.

R¹ is preferably a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by halogen (e.g., methyl, ethyl). R² is preferably ahydrogen atom, a C₁₋₆ alkyl group optionally substituted by halogen(e.g., methyl, ethyl), a C₁₋₆ alkoxy group optionally substituted byhalogen (e.g., methoxy, ethoxy). R³ is preferably a hydrogen atom, ahalogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodineatom), a C₁₋₆ alkoxy group optionally substituted by halogen (e.g.,methoxy, ethoxy). R⁴ is preferably a hydrogen atom, a C₁₋₆ alkyl groupoptionally substituted by halogen (e.g., methyl, ethyl). R⁵ ispreferably a hydrogen atom, a halogen atom (e.g., fluorine atom,chlorine atom, bromine atom, iodine atom), a C₁₋₆ alkyl group optionallysubstituted by halogen (e.g., methyl, ethyl), a C₁₋₆ alkoxy groupoptionally substituted by halogen (e.g., methoxy, ethoxy). R⁶ ispreferably a hydrogen atom, a C₁₋₆ alkyl group optionally substituted byhalogen (e.g., methyl, ethyl). R⁷ is preferably a hydrogen atom, a C₁₋₆alkyl group optionally substituted by halogen (e.g., methyl, ethyl).

R¹ is particularly preferably a hydrogen atom or a C₁₋₆ alkyl group. R²is particularly preferably a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆alkoxy group. R³ is particularly preferably a hydrogen atom, a halogenatom or a C₁₋₆ alkoxy group. R⁴ is particularly preferably a hydrogenatom or a C₁₋₆ alkyl group. R⁵ is particularly preferably a hydrogenatom, a halogen atom or a C₁₋₆ alkyl group. R⁶ is particularlypreferably a hydrogen atom or a C₁₋₆ alkyl group. R⁷ is particularlypreferably a hydrogen atom or a C₁₋₆ alkyl group.

In the formula (I), A can be classified into the following embodiments.

(i) A is represented by the formula (A-1) wherein both R¹ and R³ arehydrogen atoms, R² is a halogen atom, a C₁₋₆ alkyl group optionallysubstituted by halogen or a C₁₋₆ alkoxy group optionally substituted byhalogen.(ii) A is a pyridyl group having at least one substituent, representedby the formula (A-1) or represented by the formula (A-2), wherein one ofR¹ and R³ is a halogen atom, a C₁₋₆ alkyl group optionally substitutedby halogen or a C₁₋₆ alkoxy group optionally substituted by halogen, andthe other is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl groupoptionally substituted by halogen or a C₁₋₆ alkoxy group optionallysubstituted by halogen, R² is a hydrogen atom, a halogen atom, a C₁₋₆alkyl group optionally substituted by halogen or a C₁₋₆ alkoxy groupoptionally substituted by halogen, R⁴ and R⁶ are each a hydrogen atom, ahalogen atom or a C₁₋₆ alkyl group optionally substituted by halogen, R⁵is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group optionallysubstituted by halogen or a C₁₋₆ alkoxy group optionally substituted byhalogen, and R⁷ is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by halogen.

Another preferable embodiment of A in the formula (I) is the formula

wherein R¹, R² and R³ are as defined above, and show preferableembodiments of the corresponding substituents in the formula (I). Thepyridyl group of a partial structure (A-3) has, besides methyl group, atleast one substituent R¹, R² or R³. In the partial structure (A-3), atleast one of R¹, R² and R³ is not a hydrogen atom.

As the “pyridyl group having at least one substituent” for A, preferredis the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above, and showpreferable embodiments of the corresponding substituents in the formula(I). In a partial structure (A-2a), at least one of R⁴ and R⁵ is not ahydrogen atom, and in the partial structure (A-2b), at least one of R⁶and R⁷ is not a hydrogen atom.

Particularly preferable embodiment of compound (I) is a compoundrepresented by the following formula (Ia) or (Ib) or a salt thereof.

Here, preferable embodiments of each substituent in the formulas (Ia)and (Ib) are those of the corresponding substituent in the formula (I).

Particularly preferable other embodiments of compound (I) are compoundsrepresented by the following formula (Ia-1), the formula (Ia-2), theformula (Ib) and the formula (Ic) and salts thereof.

Here, preferable embodiments of each substituent in the formulas (Ia-1),the formula (Ia-2), the formula (Ib) and the formula (Ic) are those ofthe corresponding substituent in the formula (I). However, at least oneof R¹ and R³ in the formula (Ia-1) is not a hydrogen atom, R² in theformula (Ia-2) is not a hydrogen atom, at least one of R⁴ and R⁵ in theformula (Ib) is not a hydrogen atom, and at least one of R⁶ and R⁷ inthe formula (Ic) is not a hydrogen atom.

Specifically, R¹ and R³ in the formula (Ia-1) are the same or differentand each is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl groupoptionally substituted by halogen or a C₁₋₆ alkoxy group optionallysubstituted by halogen. Preferred as R¹ of the formula (Ia-1) is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by halogen,particularly preferably a hydrogen atom or a C₁₋₆ alkyl group. Preferredas R³ of the formula (Ia-1) is a hydrogen atom, a halogen atom or a C₁₋₆alkoxy group optionally substituted by halogen, particularly preferablya hydrogen atom, a halogen atom or a C₁₋₆ alkoxy group.

R² of the formula (Ia-2) is a hydrogen atom, a halogen atom, a C₁₋₆alkyl group optionally substituted by halogen or a C₁₋₆ alkoxy groupoptionally substituted by halogen. Preferred as R² of the formula (Ia-2)is a hydrogen atom, a C₁₋₆ alkyl group optionally substituted by halogenor a C₁₋₆ alkoxy group optionally substituted by halogen, particularlypreferably a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group.

R⁴ of the formula (Ib) is a hydrogen atom, a halogen atom, a C₁₋₆ alkylgroup optionally substituted by halogen. Preferred as R⁴ is a hydrogenatom or a C₁₋₆ alkyl group optionally substituted by halogen,particularly preferably a hydrogen atom or a C₁₋₆ alkyl group.

R⁵ of the formula (Ib) is a hydrogen atom, a halogen atom or a C₁₋₆alkyl group optionally substituted by halogen or a C₁₋₆ alkoxy groupoptionally substituted by halogen. Preferred as R⁵ is a hydrogen atom, ahalogen atom or a C₁₋₆ alkyl group optionally substituted by halogen,particularly preferably a hydrogen atom, a halogen atom or a C₁₋₆ alkylgroup.

R⁶ of the formula (Ic) is a hydrogen atom, a halogen atom or a C₁₋₆alkyl group optionally substituted by halogen. Preferred as R⁶ is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by halogen,particularly preferably a hydrogen atom or a C₁₋₆ alkyl group.

R⁷ of the formula (Ic) is a hydrogen atom or a C₁₋₆ alkyl groupoptionally substituted by halogen. Preferred as R⁷ is a hydrogen atom ora C₁₋₆ alkyl group optionally substituted by halogen, particularlypreferably a hydrogen atom or a C₁₋₆ alkyl group.

Among those mentioned above, the formula (Ia-2) is particularlypreferable.

Of compounds (I), the following compounds are preferable.

-   1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{1-[(5-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-1-[(5-fluoro-6-methylpyridin-2-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-1-[(5-fluoro-4-methylpyridin-2-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-1-[(5-fluoro-4-methoxypyridin-2-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-1-[(5-fluoro-6-methylpyridin-3-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{1-[(4,6-dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{1-[(5-chloropyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{1-[(5,6-dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{1-[(4,5-dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof, and-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof.

As compound (I), the following compounds are particularly preferable.

-   1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof,-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof, and-   1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof.

Examples of the salt of compound (I) include metal salt, ammonium salt,salts with organic bases, salts with inorganic bases, salts with organicacids, salts with basic or acidic amino acids and the like. Preferableexamples of metal salt include alkali metal salts such as sodium salt,potassium salt and the like; alkaline earth metal salts such as calciumsalt, magnesium salt, barium salt and the like; aluminum salt and thelike. Preferable examples of the salt with organic base include a saltwith trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine and the like. Preferableexamples of the salt with inorganic acid include a salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like. Preferable examples of the salt withorganic acid include a salt with formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Preferable examples of the salt with basic amino acid includea salt with arginine, lysin, ornithine and the like. Preferable examplesof the salt with acidic amino acid include a salt with aspartic acid,glutamic acid and the like. Of these, pharmaceutically acceptable saltsare preferable. For example, when a compound contains an acidicfunctional group, inorganic salts such as alkali metal salt (e.g.,sodium salt, potassium salt etc.), alkaline earth metal salt (e.g.,calcium salt, magnesium salt, barium salt etc.) and the like, ammoniumsalt and the like can be mentioned; and when a compound contains a basicfunctional group, for example, salts with inorganic acid such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like, or salts with organic acid such as aceticacid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid and the like can be mentioned.

The production methods of compound (I) in the present invention areexplained. The compounds (II)-(XXXIII) in the formula may form salts,and as such salts, for example, those similar to the salts of compound(I) can be mentioned. While the compounds obtained in respective stepscan be used for the next reaction in the form of a reaction mixture or acrude product, they can also be easily isolated and purified from thereaction mixture by a known separation and purification means, such asrecrystallization, distillation, chromatography and the like.

Compound (II) wherein R⁸ is a C₁₋₄ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl and the like can be produced according to amethod known per se, such as the method described in Chem. Pharm. Bull.,vol. 49, p. 1406 (2001), Tetrahedron Letters, vol. 35, p. 5989 (1994)and the like or a method analogous thereto.

Compound (III) wherein each symbol is as defined above can be producedby fluorinating compound (II) with a fluorinating reagent such asN-fluoropyridinium salt, xenon difluoride and the like. The amount ofthe fluorinating reagent to be used is 0.75-10 equivalents, preferably1-5 equivalents, relative to compound (II). This reaction isadvantageously carried out using a solvent inert to the reaction. Whilethe solvent is not particularly limited as long as the reactionproceeds, hydrocarbons such as benzene, toluene and the like,tetrahydrofuran, diethyl ether, acetonitrile and the like or a mixedsolvent thereof and the like is preferable. While the reaction timevaries depending on the reagents and solvent to be used, it is generally10 min to 24 hr, preferably 30 min to 12 hr. The reaction temperature isgenerally −78° C. to 100° C., preferably −20° C. to 60° C. In addition,it is possible to introduce a fluorine group by stepwise reactions, forexample, bromination with N-bromosuccinimide (NBS) and the like,followed by conversion to a fluorine group by substitution reaction.

Compound (IV) can be produced by reducing compound (III) with a reducingagent such as lithium aluminum hydride, diisobutylaluminum hydride,sodium borohydride, calcium borohydride and the like. As the reducingagent, diisobutylaluminum hydride is particularly preferable. The amountof the reducing agent to be used is 0.75-10 equivalents, preferably 1-5equivalents, relative to compound (III).

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as hydrocarbons such as benzene,toluene and the like, ethers such as tetrahydrofuran, diethyl ether,etc. and the like and a mixed solvent thereof and the like arepreferable. While the reaction time varies depending on the reagents andsolvents to be used, it is generally 10 min to 24 hr, preferably 30 minto 8 hr. The reaction temperature is generally −78° C. to 100° C.,preferably −78° C. to 25° C.

Compound (V) can be produced by reacting compound (IV) with an oxidantsuch as chromic acid-pyridine complex, pyridinium chlorochromate,manganese dioxide, sulfur trioxide-pyridine complex,tetra-n-propylammonium perruthenate and the like. As the oxidant,manganese dioxide, sulfur trioxide-pyridine complex ortetra-n-propylammonium perruthenate is preferable. This oxidationreaction can be performed, for example, according to the methoddescribed in Synthesis, p. 639 (1994).

Compound (VII) can be produced by reacting compound (V) with a compoundrepresented by the formula (VI)

wherein X is a halogen atom such as a fluorine atom, a chlorine atom andthe like, and the other symbol is as defined above. The amount ofcompound (VI) to be used is 0.75-10 mol, preferably 1-3 mol, per 1 molof compound (V).

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the like,ethers such as tetrahydrofuran and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like, acetonitrileand the like or a mixed solvent thereof and the like are preferable.

Use of a base is effective for the reaction. As the base, for example,inorganic bases such as sodium hydride, sodium hydroxide, potassiumhydroxide and the like, basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogen carbonate and the like,metal bases such as potassium ethoxide, potassium tert-butoxide, sodiummethoxide, sodium ethoxide and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, and the like canbe mentioned. The amount of the base to be used is 0.8 to 10 mol,preferably 1 to 5 mol, per 1 mol of compound (V). The reaction can alsobe carried out and is advantageous in the co-presence of a crown ether.As the crown ether, for example, 15-crown-5-ether, 18-crown-6-ether andthe like can be mentioned. The amount of the crown ether to be used is0.01 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (V). Whilethe reaction time varies depending on the reagents and solvent to beused, it is generally 1 min to 48 hr, preferably 10 min to 8 hr. Thereaction temperature is generally −20° C. to 100° C., preferably 0° C.to 50° C.

Compound (I) wherein each symbol is as defined above can be producedusing compound (VII) and methylamine or a salt thereof, by a reductiveamination reaction analogous to the method described in Jikken KagakuKoza (Courses in Experimental Chemistry), vol. 14-III, p. 1380-1385(published by MARUZEN CO., LTD.) and the like. In addition, compound(II) can also be produced according to the following method, andcompound (I) can be produced using a method similar to the methoddescribed above.

Compound (VIII) wherein each symbol is as defined above can be producedaccording to a method known per se, for example, the methods describedin Tetrahedron Letters, vol. 13, p. 5337 (1972), Heterocycles, vol. 7,p. 77 (1977), Chem. Pharm. Bull., vol. 27, p. 2857 (1979), J. Org.Chem., vol. 62, p. 2649 (1997) and the like, or a method analogousthereto.

Compound (IX) wherein each symbol is as defined above can be produced byreacting compound (VIII) with N-bromosuccinimide (NBS).N-Bromosuccinimide (NBS) is preferably used in about one equivalentrelative to compound (VIII), and the reaction is preferably carried outunder an inert gas atmosphere such as nitrogen, argon and the like.

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as ethers (e.g., tetrahydrofuran,diethyl ether and the like), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide and the like) and the like, a mixed solventthereof and the like are preferable. While the reaction time variesdepending on the reagents and solvent to be used, it is generally 10 minto 24 hr, preferably 5 to 12 hr. The reaction temperature is generally−78° C. to 80° C., preferably −78° C. to 30° C.

Addition of a base is sometimes effective for the reaction. While thebase to be used is not limited as long as the reaction proceeds, organicbases such as pyridine, picoline, lutidine and the like, and the likecan be mentioned. The amount of the organic base to be used is 0.001 to10 equivalents, preferably 0.001 to 0.1 equivalent, per compound (VIII).

Compound (X) wherein R⁹ is a pyrrole-protecting group and other symbolsare as defined above can be produced by protecting pyrrole nitrogen ofcompound (IX). The pyrrole-protecting group is not particularly limited,and examples thereof include a tert-butoxycarbonyl group (BOC group), abenzyloxycarbonyl group (Cbz group), an aryl or a heteroarylsulfonylgroup, a benzyl group, a triisopropylsilyl group and the like.

This protection reaction can be performed according to a method knownper se, for example, a method analogous to the method described inProtective Groups in Organic Synthesis, 3^(rd) Ed., Theodora W. Greene,Peter G. M. Wuts, pp. 494-653, Wiley-Interscience (1999) and the like.

Compound (XII) wherein each symbol is as defined above can be producedby reacting compound (X) with a compound represented by the formula(XIa)

wherein each symbol is as defined above, or various ester derivatives ofthe formula (XIa) according to the method described in SyntheticCommunications, vol. 11, page 513 (1981), or a method analogous thereto.In addition, can be produced by reacting compound (X) with a compoundrepresented by the formula (XIb)

wherein R is an alkyl group or an aryl group, according to the methoddescribed in Synthesis, vol. 7, pages 564-565 (1986) or a methodanalogous thereto. Examples of the “alkyl group” for R include a methylgroup and an n-butyl group, and examples of the “aryl group” include aphenyl group.

Compound (II) wherein each symbol is as defined above can be producedfrom compound (IX) according to a method similar to the method forproducing compound (XII) from compound (X). Alternatively, compound (II)can be produced from compound (XII) by a method known per se, forexample, the method described in Protective Groups in Organic Synthesis,3^(rd) Ed., Theodora W. Greene, Peter G. M. Wuts, pp. 494-653,Wiley-Interscience (1999), and the like, by removing a pyrrolenitrogen-protecting group. In addition, compound (I) can also beproduced according to the following method.

Compound (XIII) wherein each symbol is as defined above can be producedfrom compound (III) according to a method similar to the method forproducing compound (VII) from compound (V).

Compound (XIV) wherein each symbol is as defined above can be producedfrom compound (XIII) according to a method similar to the method forproducing compound (IV) from compound (III).

Compound (VII) wherein each symbol is as defined above can be producedfrom compound (XIV) according to a method similar to the method forproducing compound (V) from compound (IV).

Compound (I) can be produced from compound (VII) by a method similar tothe method described above. Alternatively, compound (I) can also beproduced from compound (XIV) according to a method including reactingmethylamine via halogenation and methanesulfonylation, a methodincluding condensing with methylamine protected by Boc, etc., followedby deprotection and the like. In addition, compound (I) can also beproduced according to the following method.

Compound (XV) as defined above can be produced from compound (V)according to a method similar to the method for producing compound (I)from compound (VII).

Compound (XVI) wherein R¹⁰ is an amino-protecting group can be producedby protecting the amino group of compound (XV). Examples of theamino-protecting group include, but is not particularly limited to, atert-butoxycarbonyl group (BOC group), a benzyloxycarbonyl group (Cbzgroup), a 2,4-dimethoxybenzyl group and the like. This protectionreaction can be carried out according to a method known per se, forexample, the method described in Protective Groups in Organic Synthesis,3^(rd) Ed., Theodora W. Greene, Peter G. M. Wuts, pp. 494-653,Wiley-Interscience (1999) and the like.

Compound (XVII) wherein each symbol is as defined above can be producedfrom compound (XVI) according to a method similar to the method forproducing compound (VII) from compound (V).

Compound (I) can be produced by removing the amino-protecting group fromcompound (XVII) by a method known per se, for example, the methoddescribed in Protective Groups in Organic Synthesis, 3rd Ed., TheodoraW. Greene, Peter G. M. Wuts, pp. 494-653, Wiley-Interscience (1999) andthe like. Compound (V) can also be produced by the following method.Furthermore, compound (I) can be produced using a method similar to themethod described above.

Compound (XVIII) can be produced according to a method known per se, forexample, the method described in Journal of Organic Chemistry (J. Org.Chem.), vol. 55, p. 6317 (1990) and the like, or a method analogousthereto.

Compound (XIX) wherein each symbol is as defined above can be producedfrom compound (XVIII) according to a method similar to the method forproducing compound (X) from compound (IX).

Compound (XX) wherein each symbol is as defined above can be producedfrom compound (XIX) according to a method similar to the method forproducing compound (XII) from compound (X).

Compound (XXI) can be produced from compound (XX) according to a methodsimilar to the method for producing compound (II) from compound (XII).Alternatively, compound (XXI) wherein each symbol is as defined abovecan be produced from compound (XVIII) according to a method similar tothe method for producing compound (XII) from compound (X).

Compound (V) can be produced from compound (XXI) according to a methodsimilar to the method for producing compound (III) from compound (II).In addition, compound (V) can also be produced according to thefollowing method. Further, compound (I) can be produced using a methodsimilar to the method described above.

Compound (XXII) wherein each symbol is as defined above can be producedaccording to a method known per se, for example, the method described inTetrahedron Letters, vol. 40, p. 4905-4908 (1999) and the like, or amethod analogous thereto.

Compound (XXIII) wherein R¹¹ is a hydroxy-protecting group, and othersymbols are as defined above can be produced, for example, according tothe method described in Organic Biomolecular Chemistry (Org. Biomol.Chem.), vol. 1, p. 3527-3534 (2003) and the like by reacting compound(XXII) with bromo (or chloro, iodo) difluoroacetic acid ester, andprotecting the resulting hydroxy group. The hydroxy-protecting group isnot particularly limited as long as the reaction proceeds, andpreferable examples include a tosyl group, a mesyl group and the like.

Compound (XXIV) wherein R¹² is an amide-protecting group, and othersymbols are as defined above can be produced by subjecting compound(XXIII) to cyclization reaction via deprotection of an amino group, andprotecting the amide group. The conditions of the amino groupdeprotection and cyclization are not particularly limited as long as thereaction proceeds, and examples thereof include reaction conditions forsimultaneous cyclization and deprotection in a hydrogen chloride-ethylacetate solution and the like. The amide-protecting group is not limitedas long as the reaction proceeds, and preferable examples include atert-butoxycarbonyl group (BOC group) and the like.

Compound (XXVI) wherein each symbol is as defined above can be producedby reacting compound (XXIV) with a compound represented by the formula(XXV) wherein Z is an atom or molecule imparting nucleophilicity such asLi, MgBr and the like.

Compound (XXV) can be produced in a reaction system according to, forexample, the method described in Tetrahedron Lett., vol. 21, p. 4137(1980) or Tetrahedron Lett., vol. 42, p. 8697 (2001), or a methodanalogous thereto.

The solvent of this reaction is not particularly limited as long as thereaction proceeds, and preferable solvents include hydrocarbons such asn-hexane, toluene and the like, ethers such as tetrahydrofuran, diethylether and the like and the like or a mixed solvent thereof and the like.The reaction time varies depending on the substrate and solvent to beused, and is generally 1 min to 48 hr, preferably 10 min to 24 hr.

Compound (XXVII) can be produced according to a method known per se, forexample, the method described in Tetrahedron Letters, vol. 36, p.5119-5122 (1995) and the like, or a method analogous thereto.Alternatively, compound (XXVII) can be produced by reducing compound(XXVI) and reacting the resulting compound with a base. The reducingagent to be used for this reaction is not particularly limited as longas the reaction proceeds, and preferable examples include sodiumborohydride and the like.

Examples of the base include inorganic bases such as sodium hydride,sodium hydroxide, potassium hydroxide and the like, basic salts such assodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate and the like, metal bases such as potassium ethoxide,potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like,aromatic amines such as pyridine, lutidine and the like, tertiary aminessuch as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the like, and the like. Theamount of the bases to be used is 0.8 to 20 mol, preferably 1 to 10 mol,per 1 mol of compound (XXV).

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the like,ethers such as tetrahydrofuran and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like, acetonitrileand the like or a mixed solvent thereof and the like is preferable. Thisreaction is advantageous in that it can be performed in the co-presenceof crown ethers. Examples of the crown ether include 15-crown-5-ether,18-crown-6-ether and the like. The amount of the crown ether to be usedis 0.01 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (XXVI).While the reaction time varies depending on the reagents and solvent tobe used, it is generally 1 min to 48 hr, preferably 10 min to 8 hr. Thereaction temperature is generally −78° C. to 100° C., preferably ˜10° C.to 70° C.

Compound (XXVIII) wherein each symbol is as defined above can beproduced from compound (XXVII) according to a method similar to themethod for producing compound (X) from compound (IX).

Compound (V) can be produced from compound (XXVIII), for example, by atypical formylation reaction including treating a reaction product ofoxalyl chloride with dimethylformamide, and the like. In addition,compound (V) can be produced by a method including introducing a cyanogroup and carboxylic acid and converting the resulting compound toaldehyde and the like. In addition, compound (XVI) can also be producedaccording to the following method, and compound (I) can be producedusing a method similar to the method described above.

Compound (XXIX) wherein R¹² is as defined above, and R¹³ is a halogenatom such as a chlorine atom, a bromine atom, an iodine atom and thelike can be produced according to a method known per se, for example,the method described in Journal of Organic Chemistry (J. Org. Chem.),vol. 66, p. 315 (2001) and the like, or a method analogous thereto.Examples of the amide-protecting group for R¹² include, but is notparticularly limited to, a tert-butoxycarbonyl group (BOC group), atosyl group, a benzyl group, an allyl group and the like.

Compound (XXX) wherein each symbol is as defined above can be producedby treating compound (XXIX) with a base. Examples of the base includeinorganic bases such as sodium hydride, sodium hydroxide, potassiumhydroxide and the like, basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogen carbonate and the like,metal bases such as potassium ethoxide, potassium tert-butoxide, sodiummethoxide, sodium ethoxide and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. and the like. The amountof the base to be used is 0.8 to 10 mol, preferably 1 to 5 mol, per 1mol of compound (XXIX).

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the like,ethers such as tetrahydrofuran and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like, acetonitrileand the like or a mixed solvent thereof and the like is preferable.While the reaction time varies depending on the reagents and solvent tobe used, it is generally 1 min to 48 hr, preferably 10 min to 8 hr. Thereaction temperature is generally −78° C. to 100° C., preferably −10° C.to 70° C.

Compound (XXXIa) wherein each symbol is as defined above or compound(XXXIb) wherein each symbols in the formula is as defined above can beproduced from compound (XXX) according to a method similar to the methodfor producing compound (XXVI) from compound (XXIV).

Compound (XXXII) can be produced by subjecting compound (XXXIa) orcompound (XXXIb) to deprotection and dehydrating reaction. While thereaction condition is not particularly limited, it varies depending onthe kind of the protecting group and the solvent to be used. Forexample, the deprotection and the dehydrating reaction continuouslyproceed by treating with an acid such as trifluoroacetic acid andhydrochloric acid.

Compound (XVI) wherein each symbol is as defined above can be producedby treating a compound represented by the formula (XXXIII) wherein eachsymbol is as defined above with a base such as sodium hydride,n-butyllithium and the like and reacting the resulting compound withcompound (XXXII).

The protecting group for R¹⁰ in this reaction is not particularlylimited as long as it is removable, and preferable examples include abenzyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group andthe like.

While the solvent used for this reaction is not particularly limited aslong as the reaction proceeds, hydrocarbons such as n-hexane, tolueneand the like, ethers such as tetrahydrofuran, diethyl ether and the likeor a mixed solvent thereof and the like are preferable. While thereaction time varies depending on the substrates and solvent to be used,it is generally 1 min to 48 hr, preferably 10 min to 5 hr. The reactiontemperature is generally −100° C. to 100° C., preferably −78° C. to 30°C.

Compound (I) can be isolated and purified by a known means such as phasetransfer, concentration, solvent extraction, fractionation, liquidconversion, crystallization, recrystallization, chromatography and thelike. When compound (I) is obtained as a free compound, it can beconverted to a desired salt by a method known per se or a methodanalogous thereto; conversely, when compound (I) is obtained as a salt,it can be converted into a free form or another desired salt by a methodknown per se or a method analogous thereto.

Compound (I) may be used as a prodrug. The prodrug of compound (I) meansa compound which is converted to compound (I) under the physiologicalcondition in the body by a reaction with an enzyme, gastric acid, or thelike, that is, a compound which is converted to compound (I) byenzymatic oxidation, reduction, hydrolysis, and the like; a compoundwhich is converted to compound (I) by hydrolysis with gastric acid, andthe like. The prodrug of compound (I) includes a compound wherein theamino group of compound (I) is modified with acyl, alkyl or phosphoryl(e.g., a compound wherein the amino group of compound (I) is modifiedwith eicosanoyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl or t-butyl, etc.); a compoundwherein the hydroxy group of compound (I) is modified with acyl, alkyl,phosphoric acid or boric acid (e.g., a compound wherein the hydroxygroup of compound (I) is modified with acetyl, palmitoyl, propanoyl,pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl,etc.); a compound wherein a carboxyl group of compound (I) is modifiedto ester or amide (e.g., a compound wherein a carboxyl group of compound(I) is modified to ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester or methylamide, etc.); and the like.These compounds can be produced from compound (I) by a method known perse. In addition, the prodrug of compound (I) may be a compound, which isconverted to compound (I) under the physiological conditions, asdescribed in Pharmaceutical Research and Development, Vol. 7 (MoleculeDesign), pp. 163-198 (1990), published by Hirokawa Publishing Co.

When compound (I) contains an optical isomer, a stereoisomer, aregioisomer or a rotamer, all of these isomers and a mixture of theseare also encompassed in compound (I). For example, when compound (I) hasan optical isomer, an optical isomer resolved from a racemate is alsoencompassed in compound (I). These isomers can be obtained as singleproducts according to synthesis and separation methods known per se(concentration, solvent extraction, column chromatography,recrystallization, etc.).

Compound (I) may be a crystal, and both a single crystal and crystalmixtures are encompassed in compound (I). Crystals can be produced bycrystallization according to crystallization methods known per se.

Compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate,both of which are encompassed in the compound (I).

A compound labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I and thelike) and a deuterium conversion form wherein ¹H has been converted to²H(D) are also encompassed in the compound (I).

Compound (I) or a salt thereof or a prodrug thereof of the presentinvention (hereinafter sometimes to be abbreviated as the compound ofthe present invention) have a proton pump inhibitory effect andeffectively suppress gastric acid secretion. In addition, since theyshow low toxicity (e.g., acute toxicity, chronic toxicity, genetictoxicity, reproductive toxicity, cardiotoxicity, drug interaction,carcinogenicity and the like) and high water-solubility, and aresuperior in the stability, in vivo kinetics (absorbability,distribution, metabolism, excretion and the like), and efficacyexhibition, they are useful as medicaments.

The compound of the present invention is useful for the prophylaxis ortreatment of peptic ulcer (e.g., gastric ulcer, duodenal ulcer,anastomotic ulcer, ulcer caused by non-steroidal anti-inflammatory drug,ulcer due to postoperative stress etc.); Zollinger-Ellison syndrome;gastritis; erosive esophagitis; reflux esophagitis such as erosivereflux esophagitis and the like; symptomatic gastroesophageal refluxdisease (Symptomatic GERD) such as nonerosive esophageal reflux,esophageal reflux unaccompanied by esophagitis and the like; Barrett'sesophagus; functional dyspepsia; gastric cancer (including gastriccancer associated with promoted production of interleukin-1β due to genepolymorphism of interleukin-1); stomach MALT lymphoma; hyperacidity;upper gastrointestinal bleeding caused by peptic ulcer, acute stressulcer, hemorrhagic gastritis, invasive stress (e.g., stress caused bymajor surgery requiring post-operative intensive management, orcerebrovascular disorder, head injury, multiple organ failure orextensive burn requiring intensive treatment) and the like; airwaydisorders; asthma; and the like in mammals (e.g., human, monkey, sheep,bovine, horse, dog, cat, rabbit, rat, mouse etc.), pre-anestheticadministration, eradication or assisting eradication of Helicobacterpylori and the like. As used herein, the above-mentioned refluxesophagitis (erosive esophagitis) and symptomatic gastroesophagealreflux disease (symptomatic GERD) are sometimes collectively referred tosimply as GERD.

The content of a compound of the present invention in the pharmaceuticalcomposition of the present invention is about 0.01 to 100% by weightrelative to the entire composition. Though subject to change dependingon the administration target, administration route, target disease andthe like, its dose is about 0.5 to 1,500 mg/day, preferably about 5 to150 mg/day, based on the active ingredient, when, for example, thecompound is orally administered as an anti-ulcer agent to an adult human(60 kg). The compound of the present invention may be administered oncedaily or in 2 or 3 divided portions per day.

The compound of the present invention shows low toxicity and can besafely administered orally or parenterally (e.g., topical, rectal,intravenous administrations and the like) as it is or as a preparationcontaining a pharmaceutical composition containing a pharmacologicallyacceptable carrier admixed according to a method known per se, such astablets (including sugar-coated tablets and film-coated tablets),powder, granule, capsule (including soft capsule), orally disintegratingtablet, orally disintegrating film, liquid, injection, suppository,sustained-release preparation, plaster and the like. Particularly, thecompound of the present invention is preferably administered as an oralpreparation in the form of tablet, granule, capsule and the like.

The pharmacologically acceptable carrier that may be used to produce thepharmaceutical composition of the present invention includes variousorganic or inorganic carrier substances in common use as pharmaceuticalmaterials, including excipients, lubricants, binders, disintegrants,water-soluble polymers and basic inorganic salts for solid preparations;and solvents, solubilizing agents, suspending agents, isotonizingagents, buffers and soothing agents for liquid preparations and thelike. Ordinary pharmaceutical additives such as preservatives,anti-oxidants, colorants, sweetening agents, souring agents, bubblingagents and flavorings may also be used as necessary. Such “excipients”include, for example, lactose, sucrose, D-mannitol, starch, cornstarch,crystalline cellulose, light anhydrous silicic acid, titanium oxide andthe like. Such “lubricants” include, for example, magnesium stearate,sucrose fatty acid esters, polyethylene glycol, talc, stearic acid andthe like. Such “binders” include, for example, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, crystalline cellulose, starch,polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan,low-substituted hydroxypropyl cellulose and the like. Such“disintegrants” include (1) crosspovidone, (2) what is calledsuper-disintegrants such as crosscarmellose sodium (manufactured byFMC-Asahi Chemical Industry Co. Ltd.) and carmellose calcium(manufactured by Gotoku Yakuhin) etc, (3) sodium carboxymethyl starch(e.g., product of Matsutani Chemical), (4) low-substituted hydroxypropylcellulose (e.g., product of Shin-Etsu Chemical), (5) corn starch, and soforth. Said “crosspovidone” may be any crosslinked polymer having thechemical name 1-ethenyl-2-pyrrolidinone homopolymer, includingpolyvinylpyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer, andis exemplified by Colidon CL (registered trademark; produced by BASF),Polyplasdon XL (registered trademark; produced by ISP), PolyplasdonXL-10 (registered trademark; produced by ISP), Polyplasdon INF-10(registered trademark; produced by ISP) and the like. Such“water-soluble polymers” include, for example, ethanol-solublewater-soluble polymers [e.g., cellulose derivatives such ashydroxypropyl cellulose (hereinafter also referred to as HPC) etc,polyvinylpyrrolidone and the like], ethanol-insoluble water-solublepolymers [e.g., cellulose derivatives such as hydroxypropylmethylcellulose (hereinafter also referred to as HPMC) etc., methyl cellulose,carboxymethyl cellulose sodium and the like, sodium polyacrylate,polyvinyl alcohol, sodium alginate, guar gum and the like] and the like.Such “basic inorganic salts” include, for example, basic inorganic saltsof sodium, potassium, magnesium and/or calcium. Preferred are basicinorganic salts of magnesium and/or calcium. More preferred are basicinorganic salts of magnesium. Such basic inorganic salts of sodiuminclude, for example, sodium carbonate, sodium hydrogen carbonate,disodium hydrogenphosphate and the like. Such basic inorganic salts ofpotassium include, for example, potassium carbonate, potassiumhydrogencarbonate and the like. Such basic inorganic salts of magnesiuminclude, for example, heavy magnesium carbonate, magnesium carbonate,magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate,magnesium silicate, magnesium aluminate, synthetic hydrotalcite[Mg₆Al₂(OH)₁₆.CO₃.4H₂O], and aluminum magnesium hydroxide. Preferred areheavy magnesium carbonate, magnesium carbonate, magnesium oxide,magnesium hydroxide and the like. Such basic inorganic salts of calciuminclude, for example, precipitated calcium carbonate, calcium hydroxide,etc. Such “solvents” include, for example, water for injection, alcohol,propylene glycol, macrogol, sesame oil, corn oil, olive oil and thelike. Such “solubilizing agents” include, for example, polyethyleneglycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like. Such “suspending agents” include, for example,surfactants such as stearyltriethanolamine, sodium lauryl sulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glyceryl monostearate etc; hydrophilic polymers such aspolyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium,methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose etc., and the like. Such “isotonizing agents”include, for example, glucose, D-sorbitol, sodium chloride, glycerol,D-mannitol and the like. Such “buffers” include, for example, buffersolutions of phosphates, acetates, carbonates, citrates etc, and thelike. Such “soothing agents” include, for example, benzyl alcohol andthe like. Such “preservatives” include, for example, p-oxybenzoic acidesters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroaceticacid, sorbic acid and the like. Such “antioxidants” include, forexample, sulfites, ascorbic acid, α-tocopherol and the like. Such“colorants” include, for example, food colors such as Food Color YellowNo. 5, Food Color Red No. 2, Food Color Blue No. 2 etc.; food lakecolors, red ferric oxide and the like. Such “sweetening agents” include,for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame,stevia, thaumatin and the like. Such “souring agents” include, forexample, citric acid (citric anhydride), tartaric acid, malic acid andthe like. Such “bubbling agents” include, for example, sodiumbicarbonate and the like. Such “flavorings” may be synthetic substancesor naturally occurring substances, and include, for example, lemon,lime, orange, menthol, strawberry and the like.

The compound of the present invention may be prepared as a preparationfor oral administration in accordance with a commonly-known method, by,for example, compression-shaping with a carrier such as an excipient, adisintegrant, a binder, a lubricant, or the like, and subsequentlycoating the preparation as necessary by a commonly known method for thepurpose of taste masking, enteric dissolution or sustained release. Foran enteric preparation, an intermediate layer may be provided by acommonly known method between the enteric layer and the drug-containinglayer for the purpose of separation of the two layers.

For preparing the compound of the present invention as an orallydisintegrating tablet, available methods include, for example, a methodin which a core containing crystalline cellulose and lactose is coatedwith the compound of the present invention and, where necessary, a basicinorganic salt, and then further coated with a coating layer containingan water-soluble polymer to give a composition, which is coated with anenteric coating layer containing polyethylene glycol, further coatedwith an enteric coating layer containing triethyl citrate, still furthercoated with an enteric coating layer containing polyethylene glycol, andfinally coated with mannitol to give fine granules, which are mixed withadditives and shaped.

The above-mentioned “enteric coating layer” includes, for example, alayer consisting of a mixture of one or more kinds from aqueous entericpolymer substrates such as cellulose acetate phthalate (CAP),hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetatesuccinate, methacrylic acid copolymers (e.g., Eudragit (registeredtrademark; produced by Rohm) L30D-55, Colicoat (registered trademark;produced by BASF) MAE30DP, Polyquid (registered trademark; produced bySan-yo Chemical) PA30 etc.), carboxymethylethyl cellulose, shellac andthe like; sustained-release substrates such as methacrylic acidcopolymers (e.g., Eudragit (registered trademark) NE30D, Eudragit(registered trademark) RL30D, Eudragit (registered trademark) RS30D,etc.) and the like; water-soluble polymers; plasticizers such astriethyl citrate, polyethylene glycol, acetylated monoglycerides,triacetin, castor oil and the like; and the like, and the like.

The above-mentioned “additive” includes, for example, water-solublesugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starchsaccharides, xylitol, reduced palatinose, erythritol, etc.), crystallinecellulose (e.g., Ceolas (registered trademark) KG 801, Avicel(registered trademark) PH 101, Avicel (registered trademark) PH 102,Avicel (registered trademark) PH 301, Avicel (registered trademark) PH302, Avicel (registered trademark) RC-591 (crystallinecellulose.carmellose sodium) etc.), low-substituted hydroxypropylcellulose (e.g., LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical),mixtures thereof etc.) and the like. Furthermore, binders, souringagents, bubbling agents, sweetening agents, flavorings, lubricants,colorants, stabilizers, excipients, disintegrants etc. are also used.

The compound of the present invention may be used in combination with 1to 3 other active ingredients. Such “other active ingredients” include,for example, anti-Helicobacter pylori active substances, imidazolecompounds, bismuth salts, quinolone compounds, and so forth. Examples ofthe “anti-Helicobacter pylori active substance” include penicillinantibiotic (e.g., amoxicillin, benzylpenicillin, piperacillin,mecillinam, ampicillin, temocillin, bacampicillin, aspoxicillin,sultamicillin, lenampicillin etc.), cephem antibiotic (e.g., cefixime,cefaclor etc.), macrolide antibiotic (e.g., erythromycin,clarithromycin, roxithromycin, rokitamycin, flurithromycin,telithromycin etc.), tetracycline antibiotic (e.g., tetracycline,minocycline, streptomycin etc.), aminoglycoside antibiotic (e.g.,gentamicin, amikacin etc.), imipenem and the like. Of these, penicillinantibiotic, macrolide antibiotic and the like are preferable. Such“imidazole compounds” include, for example, metronidazole, miconazoleand the like. Such “bismuth salts” include, for example, bismuthacetate, bismuth citrate, bismuth subsalicylate and the like. Such“quinolone compounds” include, for example, ofloxacin, ciploxacin andthe like. For eradication of Helicobacter pylori, a compound (I) or asalt thereof of the present invention with penicillin antibiotic (e.g.,amoxicillin and the like) and erythromycin antibiotic (e.g.,clarithromycin and the like) is preferably used.

For the purpose of eradication of Helicobacter pylori, while thecompound of the present invention has an anti-H. pylori action(bacteriostatic action or eradication action) by itself, it can enhanceantibacterial action of other antibiotics based on the pH controllingaction in the stomach and the like, and also provides an assistingeffect such as an eradication effect based on the action of theantibiotics to be used in combination. Such “other active ingredients”and the compound (I) or a salt thereof of the present invention may bemixed, prepared as a single pharmaceutical composition [e.g., tablets,powders, granules, capsules (including soft capsules), liquids,injectable preparations, suppositories, sustained-release preparations,etc.], in accordance with a commonly known method, and used incombination, and may also be prepared as separate preparations andadministered to the same subject simultaneously or at a time interval.

In addition, the compound of the present invention may be used incombination with a prokinetic drug, a drug acting on lower esophagealsphincter (e.g., transientlower esophageal sphincter relaxationsuppressant etc.), ClC-2 channel opener (stimulant of intestinal juicesecretion), a histamine H₂ receptor antagonist, an antacid, a sedative,a stomachic or a non-steroidal anti-inflammatory drug (NSAID). As the“prokinetic drug”, for example, domperidone, metoclopramide, mosapride,itopride, tegaserod and the like can be mentioned. As the “a drug actingon lower esophageal sphincter”, for example, GABA-B receptor agonistssuch as baclofen, an optically active form thereof and the like,glutamine receptor antagonists and the like can be mentioned. As the“ClC-2 channel opener (stimulant of intestinal juice secretion)”,lubiprostone and the like can be mentioned. As the “histamine H₂receptor antagonist”, cimetidine, ranitidine, famotidine, roxatidine,nizatidine, lafutidine and the like can be mentioned. As the “antacid”,sodium hydrogen carbonate, aluminum hydroxide and the like can bementioned. As the “sedatives”, diazepam, chlordiazepoxide and the likecan be mentioned. As the “stomachic”, gentiana, swertia japonica,diastase and the like can be mentioned. As the “non-steroidalanti-inflammatory drug”, for example, aspirin, indomethacin, ibuprofen,mefenamic acid, diclofenac, etodorac, piroxicam, celecoxib and the likecan be mentioned.

A prokinetic drug, a drug acting on lower esophageal sphincter, a ClC-2channel opener (stimulant of intestinal juice secretion), a histamine H₂receptor antagonist, an antacid, a sedative, a stomachic or anon-steroidal anti-inflammatory drug and compound (I) or a salt thereofof the present invention may be mixed, prepared as a singlepharmaceutical composition [e.g., tablets, powders, granules, capsules(including soft capsules), liquids, injections, suppositories,sustained-release preparations, etc.] according to a method known per sefor combined use, or may also be prepared as separate preparations andadministered to the same subject simultaneously or in a time-lag manner.

The compound of the present invention may be used in combination withthe following drugs.

(i) proton pump inhibitor, for example, omeprazole, esomeprazole,pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole;

(ii) oral antacid combination agent, for example, Maalox, Aludrox andGaviscon;

(iii) mucous membrane protector, for example, polaprezinc, ecabe sodium,rebamipide, teprenone, cetraxate, sucralfate, chloropylline-copper andplaunotol;

(iv) antigastric agent, for example, anti-gastrin vaccine, itriglumideand Z-360;

(v) 5-HT₃ antagonist, for example, dolasetron, palonosetron, alosetron,azasetron, ramosetron, mitrazapine, granisetron, tropisetron, E-3620,ondansetron and indisetron;

(vi) 5-HT₄ agonist, for example, tegaserod, mosapride, cinitapride andoxtriptane;

(vii) laxative agent, for example, Trifyba, Fybogel, Konsyl, Isogel,Regulan, Celevac and Normacol;

(viii) GABA_(B) agonist, for example, baclofen and AZD-3355;

(ix) GABA_(B) antagonist, for example, GAS-360 and SGS-742;

(x) calcium channel blocker, for example, aranidipine, lacidipine,falodipine, azelnidipine, clinidipine, lomerizine, diltiazem,gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine,bevantolol, nicardipine, isradipine, benidipine, verapamil,nitrendipine, barnidipine, propafenone, manidipine, bepridil,nifedipine, nilvadipine, nimodipine and fasudil;

(xi) dopamine antagonist, for example, metoclopramide, domperidone andlevosulpiride;

(xii) tachykinin (NK) antagonist, particularly, NK-3, NK-2 and NK-1antagonist, for example, nepadutant, saredutant, talnetant,(αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione(TAK-637),5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), lanepitant, dapitant and(2S,3S)-3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine;

(xiii) nitric monoxide synthase inhibitor, for example, GW-274150,tilarginine, P54, guanidioethyldisulfide and nitroflurbiprofen;

(xiv) vanilloid receptor 1 antagonist, for example, AMG-517 andGW-705498;

(xv) ghrelin agonist, for example, capromorelin and TZP-101;

(xvi) AChE inhibitor, for example, Z-338 and KW-5092.

The above-mentioned drugs (i)-(xvi) and compound (I) or a salt thereofof the present invention may be mixed, prepared as a singlepharmaceutical composition [e.g., tablets, powders, granules, capsules(including soft capsules), liquids, injections, suppositories,sustained-release preparations, etc.] according to a method known per sefor combined use, or may also be prepared as separate preparations andadministered to the same subject simultaneously or in a time-lag manner.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples, Examples and Experimental Examples,which are not to be construed as limitative.

In the following Reference Examples and Examples, the “room temperature”generally means about 10° C. to about 35° C., but it is not particularlystrictly limited. The mixing ratio of liquids shows a volume ratio.Unless otherwise specified, “%” means weight %. The yield is in mol/mol%. Silica gel column chromatography was performed using silica gel 60(0.063-0.200 mm) manufactured by MERCK, Fuji Silysia Chemical Ltd.Chromatorex (trade name) NH (described as basic silica gel columnchromatography) or Purif-Pack manufactured by MORITEX (described assilica gel column chromatography or basic silica gel columnchromatography). The melting point was measured using Yanagimoto tracemelting point measurement apparatus or Buechi trace melting pointmeasurement apparatus (B-545), and shown without amendment. For ¹H-NMRspectrum, tetramethylsilane was used as the internal standard, andVarian Gemini-200 (200 MHz), Mercury-300 (300 MHz) spectrometer, BrukerAVANCE AV300 (300 MHz) and JNM-AL400 (400 MHz) nuclear magneticresonance apparatuses JEOL DATUM (JEOL DATUM LTD.) were used for themeasurement. The following abbreviations are used for showing themeasurement results.

s: singlet, d: doublet, dd: double doublet, ddd: triple doublet, dt:double triplet, t: triplet, q: quartet, dq: double quartet, m:multiplet, br: broad, brs: broad singlet, J: coupling constant, Hz:Hertz.

Reference Example 1 tert-Butyl (2-oxoethyl)carbamate

To a mixed solution of tert-butyl (2-hydroxyethyl)carbamate (10.0 g) indimethyl sulfoxide (50 mL) and triethylamine (12.3 g) was added sulfurtrioxide pyridine complex (15.0 g) under ice-cooling, and the mixturewas stirred for 1 hr. The reaction mixture was further stirred at roomtemperature for 3 hr, 1 mol/L hydrochloric acid was added, and themixture was extracted with ethyl acetate. The separated aqueous layerwas extracted again with ethyl acetate. The combined organic layers werewashed with saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:hexane-ethyl acetate=17:3→13:7) togive the title compound as a pale-yellow oil (yield 6.50 g, 66%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 4.08 (2H, d, J=4.5 Hz), 5.19 (1H, brs),9.66 (1H, s).

Reference Example 2 Ethyl4-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}butanoate

Zinc powder (23.0 g) was washed with 0.1 mol/L hydrochloric acid,ethanol and diethyl ether, and dried under reduced pressure. Under anargon atmosphere, to a suspension of washed zinc powder intetrahydrofuran (300 mL) was added a solution of tert-butyl(2-oxoethyl)carbamate (35.0 g) in tetrahydrofuran (50 mL), ethylbromodifluoroacetate (75.9 g) was gradually added dropwise underice-cooling, and the mixture was stirred for 15 min. 1 mol/LHydrochloric acid was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The separated aqueous layer was extractedagain with ethyl acetate. Combined organic layers were washed withsaturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was dissolved in a mixed solution oftetrahydrofuran (30 mL) and pyridine (40 mL), triethylamine (19 mL),4-dimethylaminopyridine (3.35 g) and 4-methylbenzenesulfonyl chloride(39.2 g) were added at room temperature, and the mixture was stirred atfor 2 hr. The reaction mixture was concentrated under reduced pressure,and the residue was dissolved in ethyl acetate, and washed twice with 1mol/L hydrochloric acid. The separated aqueous layer was extracted againwith ethyl acetate. Combined organic layers were washed with saturatedaqueous sodium hydrogen carbonate solution, water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=4:1) to give the title compound as apale-yellow oil (yield 44.8 g, 46%).

¹H-NMR (CDCl₃) δ: 1.33 (3H, t, J=7.2 Hz), 1.46 (9H, s), 2.46 (3H, s),3.26-3.43 (1H, m), 3.71 (1H, brs), 4.28 (2H, q, J=7.1 Hz), 4.77 (1H,brs), 5.08-5.24 (1H, m), 7.35 (2H, d, J=8.1 Hz), 7.80 (2H, d, J=8.1 Hz).

Reference Example 3 tert-Butyl3,3-difluoro-4-{[(4-methylphenyl)sulfonyl]oxy}-2-oxopyrrolidine-1-carboxylate

To a solution of ethyl4-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}butanoate(44.8 g) in ethyl acetate (50 mL) was added 4 mol/L hydrogenchloride-ethyl acetate solution (100 mL), and the mixture was stirredfor 3 hr. The reaction mixture was concentrated under reduced pressure,and the residue was azeotropically distilled twice with toluene. Theobtained mixture was dissolved in acetonitrile (20 mL), triethylamine(15.6 g) was added, and the mixture was stirred for 3 hr. Di-tert-butylbicarbonate (33.6 g) and 4-dimethylaminopyridine (3.76 g) were added atroom temperature and the mixture was stirred for 1 hr. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved in ethyl acetate, and washed with 1 mol/L hydrochloric acid.The separated aqueous layer was extracted again with ethyl acetate.Combined organic layers were washed with saturated aqueous sodiumhydrogen carbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=2:1) to give the title compound as apale-yellow oil (yield 32.0 g, 80%).

¹H-NMR (CDCl₃) δ: 1.55 (9H, s), 2.48 (3H, s), 3.81-3.91 (1H, m),4.09-4.18 (1H, m), 4.94-5.06 (1H, m), 7.40 (2H, d, J=8.1 Hz), 7.83 (2H,d, J=8.1 Hz)

Reference Example 44,4-Difluoro-5-(2-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-3-yl4-methylbenzenesulfonate

To a solution of diisopropylamine (8.76 g) in tetrahydrofuran (230 mL)was added 1.6 mol/L n-butyllithium hexane solution (51 mL) at −78° C.,and the mixture was stirred for 1 hr. 2-Fluoropyridine (11.2 g) wasadded dropwise thereto, and the mixture was stirred for 2 hr. To theresultant pale-yellow suspension was slowly added dropwise a solution oftert-butyl3,3-difluoro-4-{[(4-methylphenyl)sulfonyl]oxy}-2-oxopyrrolidine-1-carboxylate(22.6 g) in tetrahydrofuran (50 mL), and the mixture was stirred for 1hr. Water was added to the reaction mixture, and the mixture was heatedto room temperature and concentrated under reduced pressure. The residuewas diluted with ethyl acetate, and washed with water. The separatedaqueous layer was extracted again with ethyl acetate. Combined organiclayers were washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained mixturewas dissolved in dichloromethane (30 mL), trifluoroacetic acid (100 mL)was added dropwise under ice-cooling, and the mixture was stirred for 4hr while allowing the mixture to warm to room temperature. The reactionmixture was concentrated under reduced pressure, diluted with ethylacetate, and a saturated aqueous sodium hydrogen carbonate solution wasadded until the mixture became neutral. The separated aqueous layer wasextracted again with ethyl acetate. Combined organic layers were washedwith saturated brine, dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent:hexane-ethyl acetate=9:1→3:1) to give the titlecompound as a colorless solid (yield 10.9 g, 51%).

¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 4.17-4.28 (1H, m), 4.42-4.54 (1H, m),5.06-5.13 (1H, m), 7.31 (1H, ddd, J=7.6, 4.9, 1.9 Hz), 7.39 (2H, d,J=7.9 Hz), 7.85 (2H, d, J=8.3 Hz), 8.22-8.31 (1H, m), 8.34-8.39 (1H, m).

Reference Example 5 2-Fluoro-3-(3-fluoro-1H-pyrrol-2-yl)pyridine

To a solution of4,4-difluoro-5-(2-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-3-yl4-methylbenzenesulfonate (18.0 g) in tetrahydrofuran (180 mL) was addedsodium borohydride (3.68 g) under ice-cooling, methanol (90 mL) wasfurther added, and the mixture was stirred for 3 hr. The reactionmixture was concentrated under reduced pressure, and the residue wasdiluted with ethyl acetate and washed with water. The separated aqueouslayer was extracted again with ethyl acetate. Combined organic layerswere washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure to give4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl4-methylbenzenesulfonate. To a suspension of sodium hydride (9.74 g) intetrahydrofuran (100 mL) was added dropwise a solution of4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl4-methylbenzenesulfonate in tetrahydrofuran (100 mL) under ice-cooling,15-crown-5 (32.2 g) was added, and the mixture was stirred for 3 hr.Saturated aqueous ammonium chloride solution was added to the reactionmixture and concentrated under reduced pressure. The residue was dilutedwith ethyl acetate, and washed with 1 mol/L hydrochloric acid. Theseparated aqueous layer was extracted again with ethyl acetate. Combinedorganic layers were washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=9:1→3:1) to give the title compound as a colorless solid (yield6.35 g, 72%).

¹H-NMR (CDCl₃) δ: 6.10 (1H, t, J=2.9 Hz), 6.69 (1H, dt, J=4.6, 3.4 Hz),7.20-7.30 (1H, m), 8.00 (1H, dt, J=4.7, 1.7 Hz), 8.25 (1H, ddd, J=10.3,7.8, 1.9 Hz), 8.69 (1H, brs).

Reference Example 62-Fluoro-3-{3-fluoro-1-[tris(1-methylethyl)silyl]-1H-pyrrol-2-yl}pyridine

To a suspension of sodium hydride (3.32 g) in tetrahydrofuran (70 mL)was added dropwise a solution of2-fluoro-3-(3-fluoro-1H-pyrrol-2-yl)pyridine (5.98 g) in tetrahydrofuran(30 mL) under ice-cooling and the mixture was stirred for 30 min.15-Crown-5 (18.3 g) and tris(1-methylethyl)silyltrifluoromethanesulfonate (25.4 g) were added, and the mixture wasstirred for 1 hr. The solvent was evaporated to a half volume underreduced pressure, water was added, and the mixture was extracted withethyl acetate. The separated aqueous layer was extracted again withethyl acetate. Combined organic layers were washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by basic silica gel columnchromatography (eluent:hexane hexane-ethyl acetate=19:1) to give thetitle compound as a pale-yellow oil (yield 10.9 g, 98%).

¹H-NMR (CDCl₃) δ: 1.04 (18H, d, J=7.0 Hz), 1.09-1.19 (3H, m), 6.17 (1H,dd, J=3.2, 1.5 Hz), 6.70 (1H, dd, J=4.8, 3.3 Hz), 7.21 (1H, ddd, J=7.3,4.9, 1.7 Hz), 7.78 (1H, ddd, J=9.3, 7.3, 2.1 Hz).

Reference Example 74-Fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde

To a solution of N,N-dimethylformamide (717 mg) in dichloromethane (20mL) was added oxalyl chloride (1.13 g) under ice-cooling under an argonatmosphere, and the mixture was stirred for 10 min. To the obtainedsuspension was added a solution of2-fluoro-3-{3-fluoro-1-[tris(1-methylethyl)silyl]-1H-pyrrol-2-yl}pyridine(1.50 g) in dichloromethane (5 mL) and the mixture was stirred underrefluxing conditions for 10 hr. The reaction mixture was cooled underice-cooling, 1 mol/L aqueous sodium hydroxide solution (30 mL) was addedand the mixture was stirred for 15 min. The solvent was evaporated to ahalf volume under reduced pressure and the residue was partitioned byadding ethyl acetate. The separated aqueous layer was extracted againwith ethyl acetate. Combined organic layers were washed with saturatedbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residual solid was washed with diisopropyl ether(30 mL) and filtered by suction to give the title compound as acolorless solid (yield 726 mg, 78%).

¹H-NMR (CDCl₃) δ: 7.29-7.40 (2H, m), 8.11 (1H, dt, J=4.8, 1.6 Hz), 8.29(1H, ddd, J=10.0, 7.9, 1.9 Hz), 9.22 (1H, brs), 9.90 (1H, s).

Reference Example 8 tert-Butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution of4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (261 mg) intetrahydrofuran (1 mL)-methanol (2 mL) was added 40% methylaminemethanol solution (4 mL) at room temperature, and the mixture wasstirred for 20 min. Sodium borohydride (142 mg) was added to thereaction mixture and the mixture was stirred for 1 hr. The reactionmixture was concentrated under reduced pressure, water (4 mL) and ethylacetate (4 mL) were added. Di-tert-butyl bicarbonate (410 mg) was addedto the obtained mixture at room temperature, and the mixture was stirredfor 1 hr. The reaction mixture was separated between ethyl acetate andan aqueous layer, and the separated aqueous layer was extracted againwith ethyl acetate. Combined organic layers were washed with saturatedbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent:hexane-ethyl acetate=9:1→3:1) to give the titlecompound as a colorless solid (yield 347 mg, 86%).

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.88 (3H, s), 4.31 (2H, s), 6.46-6.94(1H, m), 7.15-7.32 (1H, m), 8.00 (1H, dt, J=4.7, 1.7 Hz), 8.23 (1H, ddd,J=10.2, 7.9, 1.9 Hz), 8.66 (1H, brs).

Reference Example 9 2-(Benzylsulfanyl)-3-methylpyridine

To a suspension of sodium hydride (60% in oil, 1.44 g) intetrahydrofuran (45 mL) was added dropwise phenylmethanethiol (465 mg)at room temperature and the mixture was stirred for 15 min.2-Bromo-3-methylpyridine (2.0 g) was added to the reaction mixture, andthe mixture was stirred at 60° C. for 1.5 hr. The reaction mixture wasdiluted with water, and concentrated under reduced pressure. Theresidual aqueous layer was extracted twice with ethyl acetate. Combinedorganic layers were washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography(eluent:hexane-hexane-ethyl acetate=97:3) to give the title compound asa gray oil (yield 1.79 g, 72%).

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 4.49 (2H, s), 6.93 (1H, dd, J=7.6, 4.9Hz), 7.19-7.35 (5H, m), 7.39-7.48 (1H, m), 8.32 (1H, dd, J=4.9, 1.1 Hz).

Reference Example 10 3-Methylpyridine-2-sulfonyl chloride

To a solution of 2-(benzylsulfanyl)-3-methylpyridine (1.79 g) in aceticacid (16 mL)-water (8 mL) was added N-chlorosuccinimide (3.33 g) at roomtemperature, and the mixture was stirred for 2 hr. The reaction mixturewas concentrated under reduced pressure, saturated aqueous sodiumhydrogen carbonate solution was added and the mixture was extractedtwice with ethyl acetate. Combined organic layers were washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent:hexane-ethyl acetate=9:1→3:2) to give the titlecompound as a crude pale-yellow oil (yield 153 mg).

¹H-NMR (CDCl₃) δ: 2.78 (3H, s), 7.57 (1H, dd, J=7.9, 4.5 Hz), 7.82 (1H,ddd, J=7.7, 1.5, 0.8 Hz), 8.61 (1H, dd, J=4.5, 1.1 Hz).

Reference Example 11 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran(2 mL) was added a solution of tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(161 mg), 15-crown-5 (110 mg), crude 3-methylpyridine-2-sulfonylchloride (153 mg) in tetrahydrofuran (1.5 mL) at room temperature, andthe mixture was stirred at room temperature for 72 hr. The reactionmixture was diluted with water and extracted with ethyl acetate. Theseparated aqueous layer was extracted again with ethyl acetate. Combinedorganic layers were washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent:hexane-ethylacetate=9:1→11:9) to give the title compound as a colorless oil (yield113 mg, 47%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.43 (3H, s), 2.90 (3H, s), 4.32 (2H,brs), 7.20 (1H, ddd, J=7.4, 5.0, 1.7 Hz), 7.29 (1H, d, J=5.7 Hz), 7.36(1H, dd, J=7.8, 4.6 Hz), 7.61 (1H, dd, J=7.8, 0.8 Hz), 7.76-7.85 (1H,m), 8.19 (1H, ddd, J=4.9, 2.0, 1.0 Hz), 8.29 (1H, dd, J=4.5, 0.9 Hz).

Reference Example 12 2-(Benzylsulfanyl)-4-methylpyridine

To a suspension of sodium hydride (60% in oil, 512 mg) intetrahydrofuran (45 mL) was added dropwise phenylmethanethiol (1.52 g)at room temperature, 2-bromo-4-methylpyridine (2.0 g) was added, and themixture was stirred at 60° C. for 72 hr. The reaction mixture wasdiluted with water and extracted twice with ethyl acetate. Combinedorganic layers were washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography(eluent:hexane→hexane-ethyl acetate=24:1) to give the title compound asa brown oil (yield 1.40 g, 56%).

¹H-NMR (CDCl₃) δ: 2.26 (3H, s), 4.43 (2H, s), 6.82 (1H, d, J=5.1 Hz),6.99 (1H, s), 7.17-7.32 (3H, m), 7.35-7.44 (2H, m), 8.31 (1H, d, J=5.1Hz).

Reference Example 13 4-Methylpyridine-2-sulfonyl fluoride

To a solution of 2-(benzylsulfanyl)-4-methylpyridine (1.40 g) in aceticacid (10 mL)-water (5 mL) was added N-chlorosuccinimide (3.48 g) underice-cooling, and the mixture was gradually warmed to room temperatureand stirred for 4 hr. Potassium fluoride (379 mg) was added at roomtemperature and the mixture was stirred for 18 hr. The reaction mixturewas concentrated under reduced pressure, diluted with ethyl acetate andwashed with saturated aqueous sodium hydrogen carbonate solution. Theseparated aqueous layer was extracted with ethyl acetate. Combinedorganic layers were washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent:hexane-ethylacetate=4:1→11:1) to give the title compound as a crude pale-yellow oil(yield 343 mg, 30%).

¹H-NMR (CDCl₃) δ: 2.54 (3H, s), 7.50 (1H, dt, J=4.9, 0.7 Hz), 7.95 (1H,d, J=0.8 Hz), 8.69 (1H, d, J=4.9 Hz).

Reference Example 14 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension (3 mL) of sodium hydride (60% in oil, 60 mg) intetrahydrofuran were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(323 mg), 15-crown-5 (330 mg) and 4-methylpyridine-2-sulfonyl fluoride(343 mg) at room temperature, and the mixture was stirred at roomtemperature for 41 hr. The reaction mixture was diluted with water andextracted with ethyl acetate. The separated aqueous layer was extractedagain with ethyl acetate. Combined organic layers were washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give the titlecompound as a pale-yellow oil (yield 333 mg, 70%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.38 (3H, s), 2.86 (3H, s), 4.27 (2H,brs), 7.27-7.34 (3H, m), 7.36 (1H, s), 7.87 (1H, ddd, J=9.2, 7.5, 1.9Hz), 8.26 (1H, d, J=3.8 Hz), 8.45 (1H, d, J=4.9 Hz).

Reference Example 15 2-(Benzylsulfanyl)-5-fluoropyridine

To a suspension of sodium hydride (60% in oil, 440 mg) intetrahydrofuran (40 mL) was added dropwise phenylmethanethiol (1.37 g)at room temperature, 2-bromo-5-fluoropyridine (1.76 g) was added to thereaction mixture, and the mixture was stirred at 60° C. for 5 hr. Thereaction mixture was diluted with water and concentrated under reducedpressure. The residual aqueous layer was extracted twice with ethylacetate. Combined organic layers were washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent:hexane-hexane-ethyl acetate=97:3) to give the title compound asa crude brown oil (yield 244 mg).

Reference Example 16 5-Fluoropyridine-2-sulfonyl fluoride

To a solution of crude 2-(benzylsulfanyl)-5-fluoropyridine (244 mg) inacetic acid (3 mL)-water (1.5 mL) was added N-chlorosuccinimide (594 mg)under ice-cooling, and the mixture was gradually warmed to roomtemperature and stirred for 2 hr. Potassium fluoride (65 mg) was addedat room temperature and the mixture was stirred for 1 hr. The reactionmixture was concentrated under reduced pressure, diluted with water andthe mixture was extracted with ethyl acetate. The separated aqueouslayer was extracted again with ethyl acetate. Combined organic layerswere washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent:hexane-ethyl acetate=9:1→3:1)to give the title compound as a crude colorless solid (yield 69 mg,35%).

¹H-NMR (CDCl₃) δ: 7.75 (1H, ddd, J=8.7, 7.4, 2.7 Hz), 8.20 (1H, dd,J=8.8, 4.1 Hz), 8.66 (1H, d, J=2.8 Hz).

Reference Example 17 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran(2.5 mL) were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(162 mg), 15-crown-5 (220 mg) and 5-fluoropyridine-2-sulfonyl fluoride(120 mg) at room temperature, and the mixture was stirred at roomtemperature for 28 hr. The reaction mixture was diluted with water andextracted with ethyl acetate. The separated aqueous layer was extractedagain with ethyl acetate. Combined organic layers were washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent:hexane-ethyl acetate=9:1→7:3) to give the titlecompound as a pale-yellow oil (yield 69 mg, 29%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.88 (3H, s), 4.27 (2H, brs), 7.24-7.34(2H, m), 7.52 (1H, ddd, J=8.7, 7.5, 2.8 Hz), 7.68 (1H, dd, J=8.7, 4.1Hz), 7.85 (1H, ddd, J=9.2, 7.4, 2.0 Hz), 8.27 (1H, ddd, J=4.8, 1.8, 0.9Hz), 8.45 (1H, d, J=2.6 Hz).

Reference Example 18 2-(Benzylsulfanyl)-4-methoxypyridine

To a solution of 2-chloro-4-methoxypyridine (786 mg) in toluene (10 mL)were added phenylmethanethiol (683 mg), N,N-diisopropylethylamine (1.56g), tris(dibenzylideneacetone)dipalladium(0) (202 mg) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (256 mg), and themixture was stirred at 80° C. for 26 hr under an argon atmosphere. Thereaction mixture was filtered through silica gel and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-hexane-ethyl acetate=19:1) togive the title compound as an orange oil (yield 454 mg, 38%).

¹H-NMR (CDCl₃) δ: 3.79 (3H, s), 4.43 (2H, s), 6.57 (1H, dd, J=5.9, 2.5Hz), 6.68 (1H, d, J=2.3 Hz), 7.19-7.34 (3H, m), 7.36-7.44 (2H, m), 8.27(1H, d, J=5.7 Hz).

Reference Example 19 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a solution of 2-(benzylsulfanyl)-4-methoxypyridine (453 mg) in aceticacid (4 mL)-water (2 mL) was added N-chlorosuccinimide (1.10 g) underice-cooling, gradually warmed to room temperature and the mixture wasstirred for 5 hr. The reaction mixture was concentrated under reducedpressure, diluted with water and extracted twice with ethyl acetate.Combined organic layers were washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=3:1→1:1) to give crude4-methoxypyridine-2-sulfonyl chloride as a pale-yellow oil. Then, to asuspension of sodium hydride (60% in oil, 30 mg) in tetrahydrofuran (2.5mL) were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(162 mg), 15-crown-5 (165 mg) and a solution of crude4-methoxypyridine-2-sulfonyl chloride obtained above in tetrahydrofuran(2 mL) at room temperature, and the mixture was stirred for 18 hr. Thereaction mixture was diluted with water and extracted with ethylacetate. The separated aqueous layer was extracted again with ethylacetate. Combined organic layers were washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=17:3→1:1) to give the title compound as acolorless oil (yield 96 mg, yield of 2 steps 9%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.87 (3H, s), 3.84 (3H, s), 4.27 (2H,brs), 6.94 (1H, dd, J=5.6, 2.4 Hz), 7.07 (1H, d, J=2.4 Hz), 7.28 (1H,dd, J=5.3, 2.1 Hz), 7.31 (1H, d, J=5.7 Hz), 7.87 (1H, ddd, J=9.2, 7.5,1.8 Hz), 8.26 (1H, d, J=4.7 Hz), 8.39 (1H, d, J=5.7 Hz).

Reference Example 20 3-(Benzylsulfanyl)-5-fluoropyridine

To a solution of 3-bromo-5-fluoropyridine (522 mg) in toluene (5 mL)were added phenylmethanethiol (370 mg), N,N-diisopropylethylamine (831mg), tris(dibenzylideneacetone)dipalladium(0) (108 mg) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (138 mg), and themixture was stirred under an argon atmosphere at 80° C. for 2 hr. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and filtered through silica gel. Thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:hexane→hexane-ethylacetate=10:1) to give the title compound as an orange oil (yield 587 mg,90%).

¹H-NMR (CDCl₃) δ: 4.13 (2H, s), 7.23-7.33 (6H, m), 8.25-8.26 (1H, m),8.30-8.31 (1H, m).

Reference Example 21 5-Fluoropyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-5-fluoropyridine (573 mg) in aceticacid (7.5 mL)-water (2.5 mL) was added N-chlorosuccinimide (1.40 g) atroom temperature and the mixture was stirred for 1.5 hr. The reactionmixture was concentrated under reduced pressure, diluted with water andextracted twice with ethyl acetate. Combined organic layers were washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was azeotropicallydistilled with toluene and purified by silica gel column chromatography(eluent:hexane-ethyl acetate=9:1→7:3) to give the title compound as acolorless oil (yield 376 mg, 74%).

¹H-NMR (CDCl₃) δ: 8.04 (1H, ddd, J=7.0, 2.7, 2.0 Hz), 8.85 (1H, d, J=2.6Hz), 9.10 (1H, dd, J=1.1, 0.8 Hz).

Reference Example 22 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran(2 mL) were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(162 mg), 15-crown-5 (132 mg) and a solution of5-fluoropyridine-3-sulfonyl chloride (127 mg) in tetrahydrofuran (1 mL)at room temperature, and the mixture was stirred for 1 hr. The reactionmixture was diluted with water and extracted with ethyl acetate. Theseparated aqueous layer was extracted again with ethyl acetate. Combinedorganic layers were washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by basic silica gel column chromatography(eluent:hexane-ethyl acetate=9:1→7:3) to give the title compound as acolorless oil (yield 224 mg, 93%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.88 (3H, s), 4.27 (2H, s), 7.28-7.36(2H, m), 7.38 (1H, d, J=7.2 Hz), 7.73-7.86 (1H, m), 8.34 (1H, d, J=4.2Hz), 8.46 (1H, s), 8.69 (1H, d, J=2.7 Hz).

Reference Example 23 3-(Benzylsulfanyl)-4-methylpyridine

To a solution of 3-bromo-4-methylpyridine (1.0 g) in toluene (12 mL)were added phenylmethanethiol (794 mg), N,N-diisopropylethylamine (1.65g), tris(dibenzylideneacetone)dipalladium(0) (213 mg) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (269 mg), and themixture was stirred under an argon atmosphere at 80° C. for 1.5 hr. Thereaction mixture was filtered through silica gel, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:hexane-ethyl acetate=19:1→3:1→1:1) togive the title compound as a yellow oil (yield 740 mg, 59%).

¹H-NMR (CDCl₃) δ: 2.27 (3H, s), 4.07 (2H, s), 7.06 (1H, d, J=4.9 Hz),7.14-7.35 (5H, m), 8.30 (1H, d, J=5.3 Hz), 8.45 (1H, s).

Reference Example 24 4-Methylpyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-4-methylpyridine (740 mg) in aceticacid (9 mL)-water (3 mL) was added N-chlorosuccinimide (1.84 g) at roomtemperature, and the mixture was stirred for 2 hr. The reaction mixturewas concentrated under reduced pressure, diluted with water andextracted twice with ethyl acetate. Combined organic layers were washedwith saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was azeotropically distilled with tolueneand purified by silica gel column chromatography (eluent:hexane-ethylacetate=9:1→3:1) to give the title compound as a crude colorless oil(yield 676 mg).

¹H-NMR (CDCl₃) δ: 2.82 (3H, s), 7.34-7.44 (1H, m), 8.77 (1H, d, J=4.9Hz), 9.19 (1H, s).

Reference Example 25 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 24 mg) in tetrahydrofuran(2 mL) were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(161 mg), 15-crown-5 (132 mg) and a solution of crude4-methylpyridine-3-sulfonyl chloride (125 mg) in tetrahydrofuran (1 mL)at room temperature, and the mixture was stirred for 1 hr. The reactionmixture was diluted with water and extracted with ethyl acetate. Theseparated aqueous layer was extracted again with ethyl acetate. Combinedorganic layers were washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent:hexane-ethylacetate=17:3→1:1) to give the title compound as a pale-yellow oil (yield127 mg, 53%).

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.36 (3H, s), 2.92 (3H, s), 4.32 (2H,s), 7.19 (1H, d, J=5.1 Hz), 7.23-7.31 (1H, m), 7.41 (1H, brs), 7.82 (1H,dt, J=8.3, 1.9 Hz), 8.18-8.26 (2H, m), 8.58 (1H, d, J=5.1 Hz).

Reference Example 26 3-(Benzylsulfanyl)-5-methylpyridine

To a solution of 3-bromo-5-methylpyridine (888 mg) in toluene (10 mL)were added phenylmethanethiol (705 mg), N,N-diisopropylethylamine (1.47g), tris(dibenzylideneacetone)dipalladium(0)(189 mg) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (239 mg), and themixture was stirred under an argon atmosphere at 80° C. for 1.5 hr. Thereaction mixture was filtered through silica gel, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:hexane-ethyl acetate=19:1→17:3) togive the title compound as a yellow oil (yield 1.06 g, 95%).

¹H-NMR (CDCl₃) δ: 2.26 (3H, d, J=0.8 Hz), 4.09 (2H, s), 7.20-7.33 (5H,m), 7.37 (1H, dt, J=2.1, 0.8 Hz), 8.25 (1H, d, J=1.3 Hz), 8.33 (1H, d,J=2.1 Hz).

Reference Example 27 5-Methylpyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-5-methylpyridine (1.06 g) in aceticacid (15 mL)-water (5 mL) was added N-chlorosuccinimide (2.63 g) at roomtemperature and the mixture was stirred for 2 hr. The reaction mixturewas concentrated under reduced pressure, diluted with water andextracted twice with ethyl acetate. Combined organic layers were washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:hexane-ethyl acetate=19:1→17:3) togive the title compound as a colorless oil (yield 700 mg, 74%).

¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 7.96-8.22 (1H, m), 8.78 (1H, d, J=1.5Hz), 9.06 (1H, d, J=2.3 Hz).

Reference Example 28 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 24 mg) in tetrahydrofuran(3 mL) were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(323 mg), 15-crown-5 (264 mg) and a solution of4-methylpyridine-3-sulfonyl chloride (249 mg) in tetrahydrofuran (2 mL)at room temperature, and the mixture was stirred for 1 hr. The reactionmixture was diluted with water and extracted with ethyl acetate. Theseparated aqueous layer was extracted again with ethyl acetate. Combinedorganic layers were washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent:hexane-ethylacetate=9:1→1:1) to give the title compound as a pale-yellow oil (yield370 mg, 77%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.35 (3H, d, J=0.4 Hz), 2.86 (3H, s),4.26 (2H, brs), 7.26 (1H, s), 7.32 (1H, ddd, J=7.3, 5.2, 1.5 Hz), 7.38(1H, brs), 7.76-7.90 (1H, m), 8.25-8.34 (1H, m), 8.46 (1H, d, J=2.1 Hz),8.63 (1H, d, J=1.5 Hz).

Reference Example 29 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 31 mg) in tetrahydrofuran(3 mL) were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(100 mg), 15-crown-5 (170 mg), 6-methylpyridine-3-sulfonyl chloridehydrochloride (91 mg) at room temperature, and the mixture was stirredfor 1.5 hr. The reaction mixture was diluted with water and extractedwith ethyl acetate. The separated aqueous layer was extracted again withethyl acetate. Combined organic layers were washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=17:3→1:1) to give the title compound as apale-yellow oil (yield 123 mg, 83%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.62 (3H, s), 2.86 (3H, s), 4.26 (2H,s), 7.20 (1H, d, J=8.0 Hz), 7.27-7.34 (2H, m), 7.51 (1H, dd, J=8.0, 1.9Hz), 7.76-7.86 (1H, m), 8.27-8.36 (1H, m), 8.50 (1H, d, J=2.3 Hz).

Reference Example 30 3-(Benzylsulfanyl)-2-methylpyridine

To a solution of 3-bromo-2-methylpyridine (1.0 g) in toluene (12 mL)were added phenylmethanethiol (794 mg), N,N-diisopropylethylamine (1.65g), tris(dibenzylideneacetone)dipalladium(0) (213 mg) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (269 mg), and themixture was stirred under an argon atmosphere at 80° C. for 4 hr. Thereaction mixture was filtered through silica gel, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to givethe title compound as a yellow solid (yield 742 mg, 59%).

¹H-NMR (CDCl₃) δ: 2.56 (3H, s), 4.08 (2H, s), 7.03 (1H, dd, J=7.6, 5.0Hz), 7.21-7.34 (5H, m), 7.48 (1H, dd, J=7.8, 1.6 Hz), 8.30 (1H, dd,J=4.8, 1.6 Hz).

Reference Example 31 2-Methylpyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-2-methylpyridine (731 mg) in aceticacid (9 mL)-water (3 mL) was added N-chlorosuccinimide (1.81 g) at roomtemperature and the mixture was stirred for 4 hr. The reaction mixturewas concentrated under reduced pressure, diluted with water andextracted twice with ethyl acetate. Combined organic layers were washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:hexane-ethyl acetate=19:1→7:3) to givethe title compound as a colorless oil (yield 175 mg, 27%).

¹H-NMR (CDCl₃) δ: 3.03 (3H, s), 7.40 (1H, dd, J=8.1, 4.7 Hz), 8.33 (1H,dd, J=8.1, 1.7 Hz), 8.80 (1H, dd, J=4.7, 1.7 Hz).

Reference Example 32 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 34 mg) in tetrahydrofuran(2 mL) were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(226 mg), 15-crown-5 (185 mg) and a solution of2-methylpyridine-3-sulfonyl chloride (174 mg) in tetrahydrofuran (1 mL)at room temperature, and the mixture was stirred for 18 hr. The reactionmixture was diluted with water and extracted with ethyl acetate. Theseparated aqueous layer was extracted again with ethyl acetate. Combinedorganic layers were washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent:hexane-ethylacetate=17:3→1:1) to give the title compound as a yellow oil (yield 288mg, 86%).

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.61 (3H, s), 2.92 (3H, s), 4.32 (2H,s), 7.03 (1H, dd, J=8.1, 4.7 Hz), 7.21-7.26 (1H, m), 7.34 (1H, dd,J=8.1, 1.7 Hz), 7.42 (1H, brs), 7.79 (1H, ddd, J=9.2, 7.3, 2.1 Hz),8.19-8.26 (1H, m), 8.63 (1H, dd, J=4.9, 1.5 Hz).

Reference Example 33 2-(Benzylsulfanyl)-5-methoxypyridine

To a solution of 2-bromo-5-methoxypyridine (1.13 g) in toluene (15 mL)were added phenylmethanethiol (820 mg), N,N-diisopropylethylamine (1.71g), tris(dibenzylideneacetone)dipalladium(0) (220 mg) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (278 mg), and themixture was stirred under an argon atmosphere at 80° C. for 3 hr. Thereaction mixture was filtered through silica gel, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:hexane-ethyl acetate=49:1→19:1) togive the title compound as a yellow oil (yield 1.47 g, quantitative).

¹H-NMR (CDCl₃) δ: 3.83 (3H, s), 4.37 (2H, s), 6.99-7.10 (2H, m),7.19-7.31 (3H, m), 7.33-7.40 (2H, m), 8.21 (1H, dd, J=2.6, 0.9 Hz).

Reference Example 34 5-Methoxypyridine-2-sulfonyl chloride

To a solution of 2-(benzylsulfanyl)-5-methoxypyridine (1.47 g) in aceticacid (9 mL)-water (3 mL) was added N-chlorosuccinimide (3.20 g) at roomtemperature and the mixture was stirred for 2 hr. The reaction mixturewas concentrated under reduced pressure, diluted with water andextracted twice with ethyl acetate. Combined organic layers were washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:hexane-ethyl acetate=19:1→17:3) togive the title compound as a colorless solid (yield 984 mg, 79%).

¹H-NMR (CDCl₃) δ: 4.00 (3H, s), 7.38 (1H, dd, J=8.9, 2.8 Hz), 8.08 (1H,d, J=8.7 Hz), 8.43 (1H, d, J=2.8 Hz).

Reference Example 35 tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 168 mg) intetrahydrofuran (10 mL) were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(970 mg), 15-crown-5 (925 mg) and a solution of5-methoxypyridine-2-sulfonyl chloride (984 mg) in tetrahydrofuran (15mL) at room temperature, and the mixture was stirred for 30 min. Thereaction mixture concentrated under reduced pressure to a half volume,diluted with water, and extracted with ethyl acetate. The separatedaqueous layer was extracted again with ethyl acetate. Combined organiclayers were washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:hexane-ethylacetate=17:3→1:1) to give the title compound as a yellow oil (yield 1.38g, 93%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.87 (3H, s), 3.91 (3H, s), 4.26 (2H,brs), 7.16 (1H, dd, J=8.8, 2.9 Hz), 7.24-7.30 (1H, m), 7.32 (1H, d,J=5.5 Hz), 7.52 (1H, d, J=8.9 Hz), 7.87 (1H, ddd, J=9.2, 7.4, 2.1 Hz),8.23 (1H, d, J=2.4 Hz), 8.26 (1H, ddd, J=4.9, 1.9, 0.9 Hz).

Reference Example 36 5-Chloropyridin-3-yl trifluoromethanesulfonate

To a solution of 5-chloropyridin-3-ol (1.30 g) in tetrahydrofuran (50mL) were added triethylamine (1.21 g) andN-phenylbis(trifluoromethanesulfonimide) (3.93 g) at room temperature,and the mixture was stirred for 20 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withethyl acetate and washed with 1 mol/L hydrochloric acid. The separatedaqueous layer was extracted again with ethyl acetate. Combined organiclayers were washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:hexane-ethylacetate=99:1→19:1) to give the title compound as a colorless oil (yield1.73 g, 66%).

¹H-NMR (CDCl₃) δ: 7.69 (1H, t, J=2.3 Hz), 8.52 (1H, d, J=2.3 Hz), 8.64(1H, d, J=1.9 Hz).

Reference Example 37 3-(Benzylsulfanyl)-5-chloropyridine

To a solution of 5-chloropyridin-3-yl trifluoromethanesulfonate (1.73 g)in toluene (15 mL) were added phenylmethanethiol (861 mg),N,N-diisopropylethylamine (1.88 g),tris(dibenzylideneacetone)dipalladium(0) (121 mg) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153 mg), and themixture was stirred under an argon atmosphere at 80° C. for 3 hr. Thereaction mixture was filtered through silica gel, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:hexane-hexane-ethyl acetate=19:1) togive the title compound as a yellow oil (yield 1.63 g, quantitative).

¹H-NMR (CDCl₃) δ: 4.12 (2H, s), 7.21-7.36 (5H, m), 7.53 (1H, t, J=2.1Hz), 8.36 (2H, d, J=1.9 Hz).

Reference Example 38 5-Chloropyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-5-chloropyridine (1.63 g) in aceticacid (9 mL)-water (3 mL) was added N-chlorosuccinimide (3.53 g) at roomtemperature and the mixture was stirred for 2 hr. The reaction mixturewas concentrated under reduced pressure, diluted with water andextracted twice with ethyl acetate. Combined organic layers were washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was azeotropicallydistilled with toluene and purified by silica gel column chromatography(eluent:hexane-ethyl acetate=49:1→9:1) to give the title compound as acolorless oil (yield 1.26 g, 90%).

¹H-NMR (CDCl₃) δ: 8.29 (1H, t, J=2.2 Hz), 8.91 (1H, d, J=2.2 Hz), 9.12(1H, d, J=1.9 Hz).

Reference Example 39 tert-Butyl({1-[(5-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 52 mg) in tetrahydrofuran(3 mL) were added tert-butyl{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate(323 mg), 15-crown-5 (286 mg) and a solution of5-chloropyridine-3-sulfonyl chloride (318 mg) in tetrahydrofuran (2 mL)at room temperature, and the mixture was stirred for 20 min. Thereaction mixture was diluted with water and extracted with ethylacetate. The separated aqueous layer was extracted again with ethylacetate. Combined organic layers were washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=9:117:3) to give the title compound as acolorless oil (yield 391 mg, 78%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.88 (3H, s), 4.27 (2H, s), 7.26 (1H,s), 7.33 (1H, ddd, J=7.3, 5.2, 1.5 Hz), 7.61 (1H, t, J=2.1 Hz), 7.80(1H, ddd, J=9.2, 7.5, 1.9 Hz), 8.26-8.38 (1H, m), 8.50 (1H, d, J=1.9Hz), 8.76 (1H, d, J=2.3 Hz).

Example 11-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminefumarate

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(107 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) were added 4mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixturewas stirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withsaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The separated aqueous layer was extracted again withethyl acetate. Combined organic layers were washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by basic silica gel columnchromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamineas a pale-yellow oil (yield 45 mg, 54%). A solution of the obtained1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminein ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid(14 mg) in ethanol (2 mL) and the mixture was concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-ethanol togive the title compound as a white solid (yield 51 mg, 88%).

¹H-NMR (DMSO-d₆) δ: 2.35 (3H, s), 2.38 (3H, s), 3.73 (2H, s), 6.53 (2H,s), 7.32-7.39 (1H, m), 7.48 (1H, d, J=5.7 Hz), 7.63 (1H, dd, J=7.8, 4.4Hz), 7.74-7.83 (1H, m), 7.93 (1H, d, J=7.6 Hz), 8.27 (1H, d, J=4.2 Hz),8.41 (1H, d, J=4.5 Hz), 3H not detected.

Example 2 1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine hydrochloride

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(333 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/Lhydrogen chloride-ethyl acetate solution (3 mL), and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethyl acetate-ethanol to give the title compound as a white solid(yield 191 mg, 66%).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.56 (3H, s), 4.05 (2H, s)., 7.45 (1H,ddd, J=7.3, 5.0, 1.7 Hz), 7.54 (1H, s), 7.59-7.66 (1H, m), 7.77-7.90(2H, m), 8.33-8.40 (1H, m), 8.55 (1H, d, J=4.9 Hz), 9.11 (2H, brs)

Example 31-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(69 mg) in ethyl acetate (1.5 mL) and 2-propanol (1 mL) was added 4mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixturewas stirred at room temperature for 2.5 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethyl acetate-ethanol to give the title compound as a white solid(yield 31 mg, 51%).

¹H-NMR (DMSO-d₆) δ: 2.58 (3H, s), 4.07 (2H, s), 7.41-7.49 (1H, m), 7.80(1H, d, J=5.5 Hz), 7.82-7.91 (2H, m), 8.05 (1H, dt, J=8.6, 2.8 Hz), 8.36(1H, ddd, J=4.9, 1.9, 0.9 Hz), 8.78 (1H, d, J=2.8 Hz), 8.97 (2H, brs).

Example 41-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(94 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/Lhydrogen chloride-ethyl acetate solution (2 mL), and the mixture wasstirred at room temperature for 4 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethyl acetate-ethanol to give the title compound as a white solid(yield 65 mg, 79%).

¹H-NMR (DMSO-d₆) δ: 2.57 (3H, s), 3.87 (3H, s), 4.06 (2H, s), 7.17 (1H,d, J=2.3 Hz), 7.33 (1H, dd, J=5.7, 2.7 Hz), 7.46 (1H, ddd, J=6.9, 5.2,1.5 Hz), 7.80 (1H, d, J=5.7 Hz), 7.89 (1H, ddd, J=9.3, 7.6, 1.7 Hz),8.30-8.39 (1H, m), 8.51 (1H, d, J=5.7 Hz), 9.01 (2H, brs).

Example 51-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(224 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4Nhydrogen chloride-ethyl acetate solution (3 mL), and the mixture wasstirred at room temperature for 3 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethyl acetate-ethanol to give the title compound as a white solid(yield 127 mg, 65%).

¹H-NMR (DMSO-d₆) δ: 2.58 (3H, s), 4.05 (2H, s), 7.46-7.55 (1H, m),7.87-7.97 (2H, m), 8.03 (1H, dt, J=7.6, 2.3 Hz), 8.42 (1H, d, J=4.2 Hz),8.49 (1H, s), 9.04 (1H, d, J=2.3 Hz), 9.09 (2H, brs).

Example 61-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminefumarate

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(127 mg) in ethyl acetate (2 mL) and 2-propanol (0.5 mL) was added 4Nhydrogen chloride-ethyl acetate solution (2 mL), and the mixture wasstirred at room temperature for 2 hr. The reaction mixture wasconcentrated under reduced-pressure, and the residue was diluted withsaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The separated aqueous layer was extracted again withethyl acetate. Combined organic layers were washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to give1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamineas a pale-yellow oil (yield 97 mg, 97%). A solution of the obtained1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminein ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid(30 mg) in ethanol (2 mL) and concentrated under reduced pressure. Theresidue was recrystallized from ethanol to give the title compound as awhite solid (yield 103 mg, 81%).

¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 2.40 (3H, s), 3.76 (2H, s), 6.53 (2H,s), 7.43 (1H, ddd, J=7.3, 5.1, 1.8 Hz), 7.52 (1H, d, J=5.1 Hz), 7.72(1H, d, J=5.7 Hz), 7.85 (1H, ddd, J=9.5, 7.4, 1.9 Hz), 8.14 (1H, s),8.32 (1H, ddd, J=4.9, 1.9, 0.9 Hz), 8.70 (1H, d, J=5.1 Hz), 3H notdetected.

Example 71-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminefumarate

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(370 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4Nhydrogen chloride-ethyl acetate solution (3 mL), and the mixture wasstirred at room temperature for 3 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withsaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The separated aqueous layer was extracted again withethyl acetate. Combined organic layers were washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to give1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamineas a pale-yellow oil (yield 256 mg, 88%). A solution of the obtained1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminein ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid(78 mg) in ethanol (2 mL) and concentrated under reduced pressure. Theresidue was recrystallized from ethanol-water to give the title compoundas a white solid (yield 288 mg, 87%).

¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 2.35 (3H, s), 3.70 (2H, s), 6.54 (2H,s), 7.50 (1H, ddd, J=7.3, 5.1, 1.9 Hz), 7.63-7.71 (2H, m), 7.90 (1H,ddd, J=9.6, 7.5, 2.0 Hz), 8.36-8.41 (1H, m), 8.42 (1H, d, J=2.3 Hz),8.76 (1H, d, J=1.3 Hz), 3H not detected.

Example 81-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine0.5 fumarate

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(123 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/Lhydrogen chloride-ethyl acetate solution (3 mL), and the mixture wasstirred at room temperature for 3 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withsaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The separated aqueous layer was extracted again withethyl acetate. Combined organic layers were washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by basic silica gel columnchromatography (eluent:hexane-ethyl acetate=1:1) to give1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamineas a colorless oil (yield 88 mg, 91%). A solution of the obtained1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminein ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid(27 mg) in ethanol (2 mL) and concentrated under reduced pressure. Theresidue was recrystallized from ethanol-water to give the title compoundas a white solid (yield 78 mg, 77%).

¹H-NMR (DMSO-d₆) δ: 2.30 (3H, s), 2.56 (3H, s), 3.61 (2H, s), 6.51 (1H,s), 7.45-7.53 (2H, m), 7.60 (1H, d, J=5.7 Hz), 7.79 (1H, dd, J=8.3, 2.3Hz), 7.91 (1H, ddd, J=9.6, 7.5, 1.9 Hz), 8.35-8.40 (1H, m), 8.48 (1H, d,J=2.3 Hz), 2H not detected.

Example 91-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminefumarate

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(288 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/Lhydrogen chloride-ethyl acetate solution (3 mL), and the mixture wasstirred at room temperature for 3 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withsaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The separated aqueous layer was extracted again withethyl acetate. Combined organic layers were washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to give1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamineas a colorless oil (yield 220 mg, 97%). A solution of the obtained1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminein ethyl acetate (3 mL) was added dropwise to a solution of fumaric acid(67 mg) in ethanol (3 mL) and concentrated under reduced pressure. Theresidue was recrystallized from ethanol to give the title compound as awhite solid (yield 253 mg, 88%).

¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 2.49 (3H, s), 3.77 (2H, s), 6.53 (2H,s), 7.31 (1H, dd, J=8.1, 4.7 Hz), 7.42 (1H, ddd, J=7.2, 5.1, 1.7 Hz),7.47 (1H, dd, J=8.3, 1.5 Hz), 7.71 (1H, d, J=5.7 Hz), 7.84 (1H, ddd,J=9.6, 7.5, 1.9 Hz), 8.28-8.34 (1H, m), 8.73 (1H, dd, J=4.7, 1.7 Hz), 3Hnot detected.

Example 101-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine hydrochloride

To a solution of tert-butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(1.38 g) in ethyl acetate (6 mL) and 2-propanol (3 mL) was added 4 mol/Lhydrogen chloride-ethyl acetate solution (9 mL), and the mixture wasstirred at room temperature for 1.5 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethanol-water to give the title compound as a white solid (yield1.06 g, 88%).

¹H-NMR (DMSO-d₆) δ: 2.54 (3H, s), 3.91 (3H, s), 4.03 (2H, s), 7.38-7.46(1H, m), 7.51-7.58 (1H, m), 7.62-7.70 (1H, m), 7.75-7.87 (2H, m), 8.33(1H, dt, J=4.7, 0.8 Hz), 8.36 (1H, d, J=3.0 Hz), 9.20 (2H, brs).

Example 111-{1-[(5-Chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

To a solution of tert-butyl({1-[(5-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate(391 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/Lhydrogen chloride-ethyl acetate solution (3 mL), and the mixture wasstirred at room temperature for 1.5 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethanol to give the title compound as a white solid (yield 298 mg,95%).

¹H-NMR (DMSO-d₆) δ: 2.57 (3H, s), 4.05 (2H, s), 7.52 (1H, ddd, J=7.3,5.1, 1.9 Hz), 7.93 (1H, ddd, J=9.6, 7.5, 2.0 Hz), 8.01 (1H, d, J=5.5Hz), 8.11 (1H, t, J=2.2 Hz), 8.43 (1H, ddd, J=4.9, 1.8, 0.8 Hz), 8.57(1H, d, J=2.1 Hz), 9.05 (1H, d, J=2.1 Hz), 9.33 (2H, brs).

Example 121-{4-Fluoro-1-[(5-fluoro-6-methylpyridin-2-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in Reference Example15, Reference Example 16, Reference Example 17 and Example 3 and using6-bromo-3-fluoro-2-methylpyridine.

Example 131-{4-Fluoro-1-[(5-fluoro-4-methylpyridin-2-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in Reference Example15, Reference Example 16, Reference Example 17 and Example 3 and using2-bromo-5-fluoro-4-methylpyridine.

Example 141-{4-Fluoro-1-[(5-fluoro-4-methoxypyridin-2-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine

tert-Butyl group is removed from 4-tert-butoxy-2,5-difluoropyridine, andthe resulting compound is methylated to give2,5-difluoro-4-methoxypyridine, which is then subjected to synthesis inthe same manner as in Reference Example 15, Reference Example 16,Reference Example 17 and Example 3.

Example 151-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in Reference Example20, Reference Example 21, Reference Example 22 and Example 5 and using3-bromo-5-methoxypyridine.

Example 161-{4-Fluoro-1-[(5-fluoro-6-methylpyridin-3-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine

5-Chloro-3-fluoro-2-methylpyridine is synthesized from5-chloro-3-fluoro-2-iodopyridine by a boronic acid coupling reaction andthe resulting compound is subjected to synthesis in the same manner asin Reference Example 20, Reference Example 21, Reference Example 22 andExample 5.

Example 171-{1-[(4,6-Dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in Reference Example15, Reference Example 16, Reference Example 17 and Example 3 and using2-bromo-4,6-dimethylpyridine.

Example 181-{1-[(5-Chloropyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in Reference Example17 and Example 3 and using 5-chloropyridine-2-sulfonyl chloride.

Example 191-{1-[(5,6-Dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in Reference Example15, Reference Example 16, Reference Example 17 and Example 3 and using6-bromo-2,3-dimethylpyridine.

Example 201-{1-[(4,5-Dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in Reference Example15, Reference Example 16, Reference Example 17 and Example 3 and using2-bromo-4,5-dimethylpyridine.

Example 211-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine

tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(751 mg) was dissolved in saturated aqueous sodium hydrogen carbonate,and extracted twice with ethyl acetate. Combined organic layers werewashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give the title compound as apale-yellow oil (yield 647 mg, 95%).

¹H-NMR (CDCl₃) δ: 2.38 (3H, s), 2.45 (3H, s), 3.64 (2H, s), 7.23-7.30(2H, m), 7.33 (1H, d, J=5.7 Hz), 7.36 (1H, s), 7.88 (1H, ddd, J=9.3,7.4, 1.9 Hz), 8.22-8.29 (1H, m), 8.45 (1H, d, J=4.5 Hz), 1H notdetected.

Example 221-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine

tert-Butyl({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(780 mg) was dissolved in saturated aqueous sodium hydrogen carbonate,and the mixture was extracted twice with ethyl acetate. Combined organiclayers were washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent:hexane-ethylacetate=3:1→3:7) to give the title compound as a pale-yellow oil (yield619 mg, 87%).

¹H-NMR (CDCl₃) δ: 2.46 (3H, s), 3.65 (2H, s), 7.28-7.36 (2H, m), 7.41(1H, dt, J=7.3, 2.2 Hz), 7.80 (1H, ddd, J=9.2, 7.4, 2.0 Hz), 8.28-8.39(1H, m), 8.48 (1H, s), 8.68 (1H, d, J=2.6 Hz), 1H not detected.

Example 231-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine fumarate

To a solution of fumaric acid (58 mg) in ethanol (2 mL) was added asolution of1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine(189 mg) in ethyl acetate (2 mL), and the mixture was concentrated underreduced pressure. The residue was recrystallized from ethanol to givethe title compound as a white solid (yield 224 mg, 91%).

¹H-NMR (DMSO-d₆) δ: 2.35-2.40 (6H, m), 3.73 (2H, s), 6.53 (2H, s), 7.44(1H, ddd, J=7.3, 5.1, 1.8 Hz), 7.49-7.55 (2H, m), 7.59 (1H, d, J=4.9Hz), 7.86 (1H, ddd, J=9.5, 7.4, 1.9 Hz), 8.27-8.39 (1H, m), 8.54 (1H, d,J=4.9 Hz), 3H not detected.

Example 241-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine succinate

To a solution of succinic acid (59 mg) in ethanol (2 mL) was added asolution of1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine(189 mg) in ethyl acetate (2 mL) and the mixture was concentrated underreduced pressure. The residue was recrystallized from ethanol-water togive the title compound as a white solid (yield 232 mg, 93%).

¹H-NMR (DMSO-d₆) δ: 2.34 (3H, s), 2.36 (4H, s), 2.37 (3H, s), 3.66 (2H,s), 7.39-7.49 (2H, m), 7.52 (1H, s), 7.55-7.63 (1H, m), 7.86 (1H, ddd,J=9.5, 7.4, 1.9 Hz), 8.34 (1H, ddd, J=4.9, 1.9, 0.9 Hz), 8.54 (1H, d,J=4.9 Hz), 3H not detected.

Example 251-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine 0.5 fumarate

To a solution of fumaric acid (36 mg) in ethanol (2 mL) was added asolution of1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine(120 mg) in ethyl acetate (2 mL) and the mixture was concentrated underreduced pressure. The residue was recrystallized from ethanol to givethe title compound as a white solid (yield 113 mg, 82%).

¹H-NMR (DMSO-d₆) δ: 2.32 (3H, s), 3.63 (2H, s), 6.52 (1H, s), 7.50 (1H,ddd, J=7.3, 5.1, 1.9 Hz), 7.67 (1H, d, J=5.7 Hz), 7.94 (1H, ddd, J=9.6,7.5, 2.0 Hz), 7.98-8.05 (1H, m), 8.31-8.42 (1H, m), 8.48 (1H, s), 9.00(1H, d, J=2.8 Hz), 2H not detected.

Example 261-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine succinate

A solution of succinic acid (46 mg) in ethanol (4 mL) was added to1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine(150 mg), and the mixture was concentrated under reduced pressure. Theresidue was recrystallized from ethanol to give the title compound as awhite solid (yield 167 mg, 85%).

¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 2.38 (4H, s), 3.64 (2H, s), 7.50 (1H,ddd, J=7.2, 5.0, 1.9 Hz), 7.66 (1H, d, J=5.7 Hz), 7.94 (1H, ddd, J=9.6,7.5, 2.0 Hz), 7.98-8.03 (1H, m), 8.34-8.42 (1H, m), 8.44-8.53 (1H, m),9.01 (4H, d), 3H not detected.

Example 271-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine L-tartrate

A solution of L-tartaric acid (59 mg) in ethanol (4 mL) was added to1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine(150 mg), and the mixture was concentrated under reduced pressure. Theresidue was recrystallized from ethanol to give the title compound as awhite solid (yield 184 mg, 88%).

¹H-NMR (DMSO-d₆) δ: 2.44 (3H, s), 3.81 (2H, s), 4.00 (2H, s), 7.51 (1H,ddd, J=7.3, 5.2, 1.9 Hz), 7.75 (1H, d, J=5.7 Hz), 7.93 (1H, ddd, J=9.5,7.4, 1.9 Hz), 8.00 (1H, dt, J=7.8, 2.3 Hz), 8.38-8.43 (1H, m), 8.49 (1H,s), 9.02 (1H, d, J=2.6 Hz), 5H not detected.

The structures of the compounds described in Reference Examples areshown in Tables 1-2.

TABLE 1

Ref. Ex. No. R^(a) R^(b) 5 H H 6

H 7 H CHO 8 H

11

14

17

19

22

25

28

29

32

35

39

TABLE 2 Structural formulas of Reference Examples 1-4

Other structural formulas of Reference Examples 9-39

The structures of the compounds described in Examples are shown in Table3.

TABLE 3

Ex. No. A addition salt 1

2

HCl 3

HCl 4

HCl 5

HCl 6

7

8

9

10

HCl 11

HCl 21

22

23

24

25

26

27

Experimental Example 1 Proton Potassium-Adenosine Triphosphatase (H⁺,K⁺-ATPase) Inhibitory Activity Test

According to the method [Biochim. Biophys. Acta, 728, 31 (1983)] ofWallmark et al., a gastric mucous membrane microsomal fraction wasprepared from the stomach of swine. First, the stomach was removed,washed with tap water, immersed in 3 mol/L brine, and the surface of themucous membrane was wiped with a paper towel. The gastric mucousmembrane was detached, chopped, and homogenized in a 0.25 mol/Lsaccharose solution (pH 6.8) containing 1 mmol/L EDTA and 10 mmol/Ltris-hydrochloric acid using polytron (Kinematica). The obtainedhomogenate was centrifuged at 20,000×g for 30 min and the supernatantwas centrifuged at 100,000×g for 90 min. The precipitate was suspendedin 0.25 mol/L saccharose solution, superimposed on a 0.25 mol/Lsaccharose solution containing 7.5% Ficoll, and centrifuged at 100,000×gfor 5 hr. The fraction containing the interface between the both layerswas recovered, and centrifugally washed with 0.25 mol/L saccharosesolution. The obtained microsomal fraction was used as a proton,potassium-adenosine triphosphatase standard product.

To 40 μL of a 50 mmol/L HEPES-tris buffer (5 mmol/L magnesium chloride,10 mmol/L potassium chloride, 10 μmol/L valinomycin, pH=6.5) containing2.5 μg/mL (based on the protein concentration) of the enzyme standardproduct was added a test compound (5 μL) dissolved in a 10% aqueousdimethyl sulfoxide solution, and the mixture was incubated at 37° C. for30 min. The enzyme reaction was started by adding 5 μL of a 2 mmol/Ladenosine triphosphate tris salt solution (50 mmol/L HEPES-tris buffer(5 mmol/L magnesium chloride, pH 6.5)). The enzyme reaction was carriedout at 37° C. for 20 min, and 15 μL of a malachite green solution (0.12%malachite green solution in sulfuric acid (2.5 mol/L), 7.5% ammoniummolybdate and 11% Tween 20 were mixed at a ratio of 100:25:2) was addedto quench the reaction. After allowing to stand at room temperature for15 min, the resulting reaction product of inorganic phosphorus withmalachite green was calorimetrically determined at a wavelength of 620nm. In addition, the amount of the inorganic phosphoric acid in thereaction solution free of potassium chloride was measured in the samemanner, which was subtracted from the inorganic phosphoric acid amountin the presence of potassium chloride to determine the proton,potassium-adenosine triphosphatase activity. The inhibitory rate (%) wasdetermined from the activity value of the control and the activityvalues of various concentrations of the test compound, and the 50%inhibitory concentration (IC₅₀) of the proton, potassium-adenosinetriphosphatase was determined. The results are shown in Table 4.

Experimental Example 2

The pKa values were calculated using Physchem Batch (Ver. 10) (AdvancedChemistry Development, Inc.). The results are shown in Table 4.

Experimental Example 3 ATP Content Test

Human liver cancer-derived cell line HepG2 (ATCC No. HB-8065) waspassaged using Dulbecco's Modified Eagle medium (DMEM; Invitrogen)containing 10% fetal bovine serum (FBS; TRACE SCIENTIFIC LTD.), 1 mmol/Lsodium pyruvate (Invitrogen), 2 mmol/L L-glutamine (Invitrogen), 50IU/mL penicillin (Invitrogen) and 50 μg/mL streptomycin (Invitrogen) at5% CO₂, 37° C. The test reagent was prepared with DMSO to 10 mM, andfurther diluted with DMEM medium containing 0.5% FBS, 1 mmol/L sodiumpyruvate, 2 mmol/L L-glutamine, 50 IU/mL penicillin and 50 μg/mLstreptomycin to a final concentration of DMSO of 0.1%. HepG2 (2×10⁴cells/well) was cultured on a 96 well white plate (Costar) with the testreagent at 5% CO₂, 37° C. After culture for one day, the intracellularATP content was measured using ATPLite™ (PerkinElmer Life Sciences). Theresults are shown in Table 4 (n23, average value SD) as a relative value(%) to control (without addition of drug).

Experimental Example 4 Caspase-3/7 Activity Test

The Caspase-3/7 activity in the cells cultured for one day by a methodsimilar to that in Experimental Example 3 was measured using Caspase-Glo3/7 Assay (Promega). The results are shown in Table 4 (n≧3, averagevalue SD) as relative activity (%) of each reagent based on the maximumvalue of Caspase-3/7 activity when exposed to Staurosporine (100%), andthe activity without addition of a test reagent (0%).

Experimental Example 5 Measurement of Perfusate pH in Anesthetized RatStomach Reperfusion Model

Jcl:SD male rats (8-week-old) were fasted for about 24 hr and used forthe experiment. The test compounds were dissolved in a DMAA:PEG400=1:1solution to the dose of 1 mL/kg. Under anesthesia with urethane (1.2g/kg, i.p.), cannulas were inserted from the duodenum and theforestomach into the stomach, the esophagus was ligated and the stomachwas reperfused with physiological saline (0.5 mL/min). The perfusate wassubjected to a continuous pH measurement using trace flow type glasselectrodes (6961-15C and 2461A-15T, HORIBA). Histamine dihydrochloride(8 mg/kg/h) was continuously administered for 1 hr or longer byintravenous infusion. After the pH was stabilized, the test compound wasintravenously administered. The pH of the perfusate was measured until 5hours after administration of the test compound. The results are shownin FIGS. 1, 2 and 3.

TABLE 4 H⁺/K⁺-ATPase inhibitory Caspase-3/7 Example activity pKa valueATP content activity No. (IC₅₀, nM) (calculated) (%, 100 μM) (%, 100 μM)2 100 7.84 85.5 −1.1 3 100 7.77 86.5 −0.5 4 140 7.79 84.5 −0.6 5 2007.73 88.9 0.3 8 180 7.81 76.7 2.4 10 280 7.79 80.0 0.9 23 83 7.84 — — 24140 7.84 — — 25 200 7.73 — — 26 130 7.73 — — 27 160 7.73 — —

From the results of Table 4, it is clear that compound (I) of thepresent invention has a superior H⁺/K⁺-ATPase inhibitory activity and alow pKa value, as well as extremely low cytotoxicity even when used at ahigh concentration. In addition, from the results of FIGS. 1, 2 and 3,it is clear that compound (I) has a moderate duration of action.

INDUSTRIAL APPLICABILITY

Compound (I) of the present invention shows a superior proton pumpinhibitory effect. Conventional proton pump inhibitors such asomeprazole, lansoprazole and the like are converted to active forms inan acidic environment of gastric parietal cells and form a covalent bondwith a cysteine residue of H⁺/K⁺-ATPase, and irreversibly inhibit theenzyme activity. In contrast, compound (I) inhibits proton pump(H⁺/K⁺-ATPase) activity in a reversible and K⁺ competitive manner, andconsequently suppresses acid secretion. Therefore, it is sometimescalled a potassium-competitive acid blocker (P-CAB), or an acid pumpantagonist (APA). Compound (I) rapidly exhibits the action and shows themaximum efficacy from the initial administration. Furthermore, itsmetabolism is less influenced by metabolic polymorphism, and variationof efficacy among patients is small. In addition, it has been found thatcompound (I) is designed to have a characteristic chemical structurewherein (i) the substituent at the 5-position of pyrrole ring is a2-F-3-pyridyl group, (ii) the substituent at the 4-position of pyrrolering is a fluorine atom, and (iii) the 1-position of pyrrole ring is a2-pyridylsulfonyl group or 3-pyridylsulfonyl group having at least onesubstituent, and such chemical structure is conducive to a strong protonpump inhibiting activity, and significantly decreases cytotoxicity.Furthermore, it is characterized in that substitution of the 4-positionof pyrrole ring by a fluorine atom in compound (I) lowers basicity (pKavalue) of methylaminomethyl moiety due to an electron withdrawing effectof the fluorine atom, and decreases the risk of toxicity expressionderived from strong basicity, and that introduction of at least onesubstituent into A of compound (I) controls the duration of actionoptimally. Hence, the present invention can provide a clinically usefulagent for the prophylaxis or treatment of peptic ulcer (e.g., gastriculcer, duodenal ulcer, anastomotic ulcer, ulcer caused by non-steroidalanti-inflammatory drug, ulcer due to postoperative stress etc.),Zollinger-Ellison syndrome, gastritis, erosive esophagitis, refluxesophagitis, symptomatic gastroesophageal reflux disease (SymptomaticGERD), Barrett's esophagus, functional dyspepsia, gastric cancer,stomach MALT lymphoma or hyperacidity; or a suppressant of uppergastrointestinal bleeding due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress; and the like. Since compound(I) shows low toxicity and is superior in water-solubility, in vivokinetics and efficacy exhibition, it is useful as a pharmaceuticalcomposition. Since compound (I) is stable even under acidic conditions,it can be administered orally as a conventional tablet and the likewithout formulating into an enteric-coated preparation. This has anadvantageous consequence that the preparation (tablet and the like) canbe made smaller, and can be easily swallowed by patients havingdifficulty in swallowing, particularly the elderly and children. Inaddition, since it is free of a sustained release effect afforded byenteric-coated preparations, onset of suppression of gastric acidsecretion is rapid, and symptoms such as pain and the like can bealleviated rapidly.

While some of the embodiments of the present invention have beendescribed in detail in the above, it will, however, be evident for thoseof ordinary skill in the art that various modifications and changes maybe made to the particular embodiments shown without substantiallydeparting from the novel teaching and advantages of the presentinvention. Such modifications and changes are encompassed in the spiritand scope of the present invention as set forth in the appended claims.

This application is based on patent application Nos. 2008-218851 and2008-269099 filed in Japan, the contents of which are incorporated infull herein by this reference.

1. A compound represented by the formula (I)

wherein A is a pyridyl group having at least one substituent:

wherein R¹, R² and R³ are each a hydrogen atom, a halogen atom, a C₁₋₆alkyl group optionally substituted by halogen or a C₁₋₆ alkoxy groupoptionally substituted by halogen, R⁴ and R⁶ are each a hydrogen atom, ahalogen atom or a C₁₋₆ alkyl group optionally substituted by halogen, R⁵is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group optionallysubstituted by halogen or a C₁₋₆ alkoxy group optionally substituted byhalogen, and R⁷ is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by halogen, or a salt thereof.
 2. The compound of claim 1,wherein A is represented by the formula (A-1) wherein R¹ and R³ are bothhydrogen atoms, and R² is a halogen atom, a C₁₋₆ alkyl group optionallysubstituted by halogen or a C₁₋₆ alkoxy group optionally substituted byhalogen, or a salt thereof.
 3. The compound of claim 2, wherein R² is aC₁₋₆ alkyl group or a C₁₋₆ alkoxy group, or a salt thereof. 4.1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof. 5.1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof. 6.1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof. 7.1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof. 8.1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,or a salt thereof.
 9. A prodrug of the compound of claim 1 or a saltthereof.
 10. A pharmaceutical composition comprising the compound ofclaim 1 or a salt thereof or a prodrug thereof.
 11. The pharmaceuticalcomposition of claim 10, which is an acid secretion inhibitor.
 12. Thepharmaceutical composition of claim 10, which is a potassium-competitiveacid blocker.
 13. The pharmaceutical composition of claim 10, which isan agent for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis, symptomaticgastroesophageal reflux disease (symptomatic GERD), Barrett's esophagus,functional dyspepsia, gastric cancer, stomach MALT lymphoma, or ulcercaused by non-steroidal anti-inflammatory drug, gastric hyperacidity orulcer due to postoperative stress; or an inhibitor of uppergastrointestinal bleeding due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress.
 14. A method for treating orpreventing peptic ulcer, Zollinger-Ellison syndrome, gastritis, refluxesophagitis, symptomatic gastroesophageal reflux disease (symptomaticGERD), Barrett's esophagus, functional dyspepsia, gastric cancer,stomach MALT lymphoma, or ulcer caused by non-steroidalanti-inflammatory drug, gastric hyperacidity or ulcer due topostoperative stress; or a method of inhibiting upper gastrointestinalbleeding due to peptic ulcer, acute stress ulcer, hemorrhagic gastritisor invasive stress, which comprises administering an effective amount ofthe compound of claim 1 or a salt thereof or a prodrug thereof to amammal.
 15. Use of the compound of claim 1 or a salt thereof or aprodrug thereof for the production of an agent for the prophylaxis ortreatment of peptic ulcer, Zollinger-Ellison syndrome, gastritis, refluxesophagitis, symptomatic gastroesophageal reflux disease (symptomaticGERD), Barrett's esophagus, functional dyspepsia, gastric cancer,stomach MALT lymphoma, or ulcer caused by non-steroidalanti-inflammatory drug, gastric hyperacidity or ulcer due topostoperative stress; or an inhibitor of upper gastrointestinal bleedingdue to peptic ulcer, acute stress ulcer, hemorrhagic gastritis orinvasive stress.